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Le succès grandissant du « flight tracking » - Cette pratique retrace les déplacements des avions à partir des signaux transmis publiquement - Le Monde

Le succès grandissant du « flight tracking » - Cette pratique retrace les déplacements des avions à partir des signaux transmis publiquement - Le Monde submitted by NoFrontiers to france [link] [comments]

Comment identifier les signaux forex très performants ?

Si vous êtes un trader novice sur les marchés Forex, vous envisagez peut-être d’utiliser les signaux forex très performants pour vous aider à spéculer sur le marché boursier. En fait, en suivant les signaux de trading Forex d’autres traders, vous pouvez économiser beaucoup de temps et d’énergie, mais vous pouvez aussi apprendre de nouvelles méthodes et stratégies de trading.
https://festivalnezrouges38.fcomment-identifier-les-signaux-forex-tres-performants/
submitted by orkke to u/orkke [link] [comments]

My smoothest landing of 2022 :)

My smoothest landing of 2022 :) submitted by Ivy_Wings to flightsim [link] [comments]

Le satellite Capstone atteint enfin la Lune après un voyage chaotique

Le satellite Capstone atteint enfin la Lune après un voyage chaotique
Lien

Ce n'était pas un voyage si facile
https://preview.redd.it/oqv9pwxq9wz91.jpg?width=1024&format=pjpg&auto=webp&s=da4e56561ed00ab544ed398579648c3200a69fa3
Le nanosatellite, qui fait office d’éclaireur pour le programme Artémis, a fini par atteindre la Lune, non sans mal. Son objectif : tester une orbite spéciale, prévue pour la station spatiale lunaire.
Non sans mal, Capstone a fini par arriver à destination, a confirmé la Nasa le 14 novembre 2022. Le nanosatellite américain Capstone a enfin atteint la Lune pour une courte mission, mais essentielle : tester une orbite spéciale autour du satellite de la Terre, qui servira ultérieurement à la future station lunaire. L’insertion de Capstone sur l’orbite a eu lieu le 13 novembre, après un périple de plus de quatre mois dans l’espace.
Capstone, dont le nom signifie « Cislunar Autonomous Positioning System Technology Operations and Navigation Experiment », tient le rôle de précurseur pour le programme Artémis — dont le but est de renvoyer des astronautes sur la Lune pendant la décennie 2020. Pour faire la jonction entre la Terre et la Lune, une station spatiale comme l’ISS est idéale.
Dans ce cadre, une orbite très prometteuse a été retenue : c’est une orbite quasi-rectiligne de halo très excentrique. Sa forme est particulière, à tel point que l’on a l’impression de voir une sorte de « collier » suspendu au cou de la Lune. C’est en tout cas vrai pour certains visuels. En réalité, la trajectoire de Capstone et la station sera bien plus complexe.
Cette configuration offre plusieurs avantages pour réduire la complexité de la mission Artémis : elle maintient en permanence une vue directe avec la Terre pour les communications ; elle demande peu d’énergie pour maintenir la station en place ; elle facilite l’accès à la surface lunaire, à divers endroits ; et elle peut servir à des missions au-delà de la Lune.

Un voyage difficile pour Capstone

Le voyage de Capstone n’a pas été sans mal. Si le point d’étape de l’agence spatiale américaine à la fin octobre était positif, signalant la réussite d’une correction de trajectoire, pour préparer la bonne insertion du nanosatellite, la situation ces dernières semaines a été délicate. En particulier, le comportement de l’engin n’était pas toujours nominal.
La Nasa l’a rappelé lors de son point d’étape, avec un véhicule qui s’est retrouvé dans un « mode de sécurité » à cause d’un problème survenu au début du mois de septembre. Ce souci a entrainé la rotation du vaisseau spatial. En cause, selon les investigations de l’agence ? Une valve défaillante dans l’un des huit propulseurs du vaisseau spatial.
Capstone, qui a exécuté une manœuvre finale le 13 novembre pour se placer sur cette orbite de halo presque rectiligne, doit fonctionner au moins six mois autour de la Lune. En parallèle, la Nasa souhaite lancer la mission Artémis 1, première étape de son programme. Ici, il s’agit de faire décoller sa super-fusée, faire le tour de la Lune, puis revenir. La mission est inhabitée. C’est une sorte de répétition générale avant le vol avec des astronautes
Pour aller plus loin 📷 Objectif Lune : où voir en temps réel le trajet de la mission Artémis 1 ?
submitted by miarrial to actutech [link] [comments]

Structure-Stereochemical-Activity-Relationships of Classical Morphinan Hetereocyles - Molecusexuality of Opioid Stereochemistry - the Morphinan in the Mirror, Part I - a well cited survey of Stereochemistry, Geometry and Sterics of the Opioid Ligands u/jtjdp r/AskChemistry

Structure-Stereochemical-Activity-Relationships of Classical Morphinan Hetereocyles - Molecusexuality of Opioid Stereochemistry - the Morphinan in the Mirror, Part I - a well cited survey of Stereochemistry, Geometry and Sterics of the Opioid Ligands u/jtjdp AskChemistry

Morphine is considered to the the Proteus of Organic Molecules.

As the first alkaloid isolated from plant matter and done so on an industrial scale, it became the Proteus of the modern pharmaceutical industry and inspired the field of natural product chemistry. The first major SAR elucidation efforts were conducted by the American NRC team of LF Small, NB Eddy and EL May beginning in 1929 in order to find morphine derivatives that had reduced addiction liability. Thus, morphine, or the search for safer mu-opioid receptor agonist analgesics, is the forefather of the field of Medicinal Chemistry and modern SAR Elucidation is based upon techniques developed during these early SAR invesgitations. --------------------------------------------------------
In one of the many ironic twists of history, white European Cartels of the 19th century forced Chinese merchants to continue purchasing their opium. When the Chinese passed some of the first drug control laws, the economic importance of Indian Opium sales to China necessitated gunboat diplomacy and sparked a brief series of wars.
After America had their own devastating Napoleonic-era conflict, the generation that fought that war, inherited a condition of morphinomimetic habituation to a degree and scale not observed since. Known as the "Soldier's Disease" it affected many Civil War veterans throughout their entire lives. The opioid crises of today is nothing new. History is cyclical and there is always something to be learned through well versed retrospectives.
I've spent 15 years of my life working as a medicinal chemist in the arena of opioid development. I've worked with all the subtypes: mu, delta, kappa, and NOP/ORL1. I've studied them on three continents and worked with them under a variety of regulatory regimes.
Unlike most professionals in the healthcare field, I'm not afraid to discuss my own personal struggles with opioid addiction, which I certainly took to "another level" and developed some monster tolerances to some novel and highly potent agonists. While I don't consider addiction to be a moral or criminal issue, it rarely improves the lives of those trapped it in its cycles. It's a disease state just like any other and, unfortunately, the responsibility for this generation's "crises" rests at the feet of my own industry.
The literature survey I present here are filled w/ sarcasm, lighthearted humor and a few personal anecdotes. There's plenty of meat and potatoes to be had. But through anthropomorphizing these quantized molecules, perhaps I can make the topic of classical morphinan SAR more fun, flippant and digestible.
Enjoy. --Deandra aka: Duchess Von D
------------------------------------------------------------------

Molecusexuality of Opioid Stereochemistry: The Morphinan In the Mirror, Part IA: non-IUPAC approved Molerotic adventure in anthropomorphic Molecular sterics

By:
Edie Norton w/ a Fire Crotch, Sufentstress of the morphinomimetic mattress, the π-pair-o-skinny-jeans molecuho, Mini-Thinny Mouse, the RemiFenny Skank, the μ-gμrμ
Dμchess Vσn δ
A well cited exploration into the Stereochemistry, Geometry and Sterics of the Opiosphere
-------
The idea for this post came about as I was working on another post about N-aralkyl substituted morphinans entitled “Tetracycles in Tiaras”. [see u/jtjdp for this post]
In prep’n for that post, I did my typical image hosting on Imgur. The concepts of cis-(1,3-diaxial) piperidine fusion, cis-B:C and trans-C:D ring fusion are important to the morphinan and polycyclic classes. As such, several of my images featured these cis/trans (molecular) orientations quite prominently. It soon earned a slew of downvotes.
I discovered the reason for this lack of opio-enthusiasm when a confused Imgurian left an interesting comment:
“Yo, why do you gotta assign genders? Can't they just make up their own minds and live their own lives w/o you forcing your own binary genders?”
For chemists out there, this certainly was hilarious, but i decided to humor this Imgurian and imagine a world where his polarimetry correct views applied to quantized matter like any other civil or fundmaental human right.
Technically these molecusexual orientations were assigned by people. While they aren’t genders as much as geometric orientations, either way, it is forcing nomenclature onto a quantized state of matter. And forced conformations are no a laughing matter.
Forcing a Fetty to be a Frannie, or a Diladdy to be a Maddy, or a Thebby to be Thaddy, is in contravention to the “UN Resolution on Stereochemical Self-Determination.”
A clear cut “heroin rights violation.
------I'm going to pause for a moment, and allow that rapid fire burst of punnery to fully set in------
But enantiomers don’t resolve themselves. They need a helping hand.
And that’s how I came up with the idea for Molecusexuality.
Clearly there is a need to explain the long history of the brave pioneering molecules that came out of the cis/trans closet long before the LGBTQ community was even a thing. Nature lead the charge. Humanity eventually followed.
There are some reactions, such as the Knoevenagel (benzaldehyde + nitroalkane + n-butylamine), which still remain in the closet, at least until the resulting nitrostyrene provides the confidence needed to stand proud outside of said closet.
The DEA has been engaging in molecular eugenics for fifty years. They split hairs on matters of cis/trans 4-methylaminorex, dextro-/levo-methorphan and countless other higgedy-piggedly matters. Forcing molecules to conform to arbitrary legal codes is as absurd as the concept of prohibition.
Statistically speaking, molecules are braver than man. This, of course, was left out by the mainstream press during Pride Month. I’m here to set the record 109.5 degrees/Tetrahedral.
I’m a medicinal chemist, self-experimentalist in the same vain as Hoffmann and Shulgin, but when it comes to morphinans and 5,9-dialkyl-6,7-benzomorphans, I’m all about the absolute configuration of C(14).
In fact, even among the 14(R)-cis-morphinans, i.e. Morphine, cis/trans isomerism is always in play within the the same molecule. The B:C rings exist in a cis-decalin fusion while the C:D rings are fused in trans-decahydroisoquinoline arrangement.
The quantum duality of cis-trans ligand-bendery among the morphinans is Quantum Pride. I’ve made only a few novel discoveries over my career. But I have made many ligands and many of those have graced my spoon.
Of the ~ 25 of these that are of the Opioid variety (especially near and dear to my blood-brain barrier), many have been chiral. As such, they involve a range of stereochemical relationships that are important to their chemical reactivity and bioactivity.
That’s only counting successes. Many were failures. And many of those were due to incorrect stereochemistry. I will share examples with you during the intermissions, entitled: “Epic Failures in Stereoisomerism.”
In humans, mu-stereotypy tends to suppress libido. Making them less sexy. What about other mammals?
While the lab mice are remaining mum as church mice on these topics, their behavior says all we need to know.
Below is a mouse on morphine.

“I’m too sexy for this lab, too sexy for this cage, too sexy for rehab…”
More murine centerfolds found here: https://doi.org/10.1111/j.1476-5381.1960.tb00277.x
This is known as a Straub tail. It has been a hallmark of mu-mediated activity since Straub first noted the phenomena in 1911. They call this a "narcotic cue." And it is still used today as indicative of mu-mediated stereotypy.
I'm here to make opioids and the average SAR narrative into a soap operatic adventure. Perhaps not as sexy as John Stamos on General Hospital, but with a little help from my brand of prose, help guide you into ligand lust. Welcome to the world of Molecu-sexuality.
This is far from a comprehensive review of the topic. If you seek a deeper dive, I recommend the works of AF Casy, PS Portoghese, NB Eddy, EL May, P Janssen, Leysen, and Van der Eycken.
As with my other chemical musings, these are finger friendly Morph-Dives into the chem. lit. They're "abbeaviated", but there's enough page flicking to advise protection. Be sure to wear thimbles (or at least lubrication), as thumbs are bound to get pricked. I am not responsible for any paper cuts.

Fundamentals

VOCAB-REHAB

Stereoisomers - isomers with same connectivity; different configuration (arrangement) of substituents
Enantiomers - mirror-image asymmetry; non-superimposable (i.e right-/left-handed morphittens); only differ by the direction (d,l or +,-) of optical rotation
Diastereomers - stereoisomers that are not mirror images; different compounds w/ diff phys properties
Asymmetric Center - tetrahedral carbon w/ sp3 hybridized orbital; capable of σ-bond; (4 different groups attached)
Stereocenter - an atom at which the interchange of two groups gives a stereoisomer
Asymmetric Carbons and cis-trans isomerism are the most common stereocenters
Cis/Trans isomerism - aka: geometric isomerism; applies to orientation of specified groups about a fixed bond, such as a fused heterocyclic morphinan system or an alkene (dbl bond) - cis = same geometric plane; trans = opposite geometric plane; in the morphinan series this refers to fixed constrained alicyclic ring fusions where the amount of rotational freedom is limited
E/Z notation - (E = opposite geometric plane, Z = same geometric plane) Using such notation would make trans-fats become E*-fats* and I don’t believe in furthering the cause of trans-fat bigotry. Thus I will be sticking to the conventional terminology using cis = same side of bond (same geometric plane) and trans to indicate the opposite.
https://i.imgur.com/dNLbPle.png [orbital hybridization chart]
Optically active/Chiral Compound - rotates plane of polarized light in polarimeter (achiral = no rotation) - chiral molec must have an enantiomer

Stereospecific Binding - SSB - The Hallmark of Morphanity

The μ-opioid receptor (MOR) is characterized by stereospecific binding (SSB). This is not the only G-protein Coupled Receptor (GPCR) that demonstrates SSB, but it was one of the first to be well recognized and is considered a classical model for the SSB of GPCRs.
There are other features that set the MOR apart from other GPCRs, such as the size of the mouth of its ligand binding pocket (active site), which allows it to fit a wide-range of diverse structures including highly flexible acyclic diphenylheptanones (methadone), the high-mol weight (but mostly planar) etonitazene, the atypical bezitramide, spirodecanones (R5260, R6890), and the most rigid and highly-constrained system in the opiosphere, the 6,14-endo-ethano bridged oripavines. (etorphine, buprenorphine). This versatile orifice will be explored later.
Lit Surveys of a number of highly affine ligands with physicochem, IC(50), K(i) data [http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x)] [https://sci-hub.se/10.1016/0014-2999(77)90334-x90334-x)
The crystalline structure of the murine MOR was elucidated in 2011, the same year I finished grad school. There are new discoveries made every day in this area. It can be difficult to keep track of them all, but the link below contains some of the highlights. The molecular dynamics and mechanics of ligand-receptor interactions and the binding modes of the lig-rec complex are important, but are beyond the scope of this monograph.
https://doi.org/10.1038/nature10954

stereospecific binding of bioreceptors
https://sci-hub.se/10.1002/ange.19600721806
Stereospecificity, that is, a preferential affinity for one enantiomer over another, depends upon the ligand’s absolute configuration. That is, the 3D arrangement of substituents as they are configured around a chiral center in real life.
As a matter of convenience and convention, the medical and pharma literature uses optical rotatory stereodescriptors when referring to enantiomers. Examples include d-(+)-amphetamine (Dexedrine) or l-(-)-amphetamine (Lamedrine).
The reason that d-amphetamine is more bioactive than its antipode is due to the receptor-preferred absolute config of its asymmetric carbon, which is configured as (S), which means the substituents about the chiral center (as designed by a convention known as CIP Priority Rules) are oriented in a counterclockwise or left-handed direction.
This is the opposite direction that dextroamphet rotates polarized light. D-(+)-amphet rotates light in a clockwise, (+), or right-handed rotation. But its substituents are oriented in a counterclockwise manner according to CIP priority rules, giving it the designation dextro-(S)-amphetamine.
The less active levo-antipode has the (R) abs config, while rotating light to the left or (-).
The optical rotation, in and of itself, does not tell you the abs config about a stereocenter. Nor does the abs config indicate the optical rotation of a compound. Bioreceptors, however, will favor a particular absolute config over another.
Absolute configuration and optical rotation are two separate concepts that are related as they are different ways of classifying stereochemistry, but are not interchangeable. They are measured/determined in different ways.
The most important is absolute configuration. This is the most fundamental property of mol geometry and changes to abs config alters the activity and optical rotation of the molecule. Configuration is determined with spectroscopy.
Optical rotation is an inherent molecular property that can be measured with polarimetry. A pure optical isomer will have a very specific value. The direction and degree that polarized light is rotated by an enantiomer is an important analytical value found in the Merck Index and the anal. chem. lit. Combined with other data, it can be used to identify and characterize optically active products and even identity unknowns.
Left-handed (like me) or counterclockwise rotation is designed levorotatory, levo-, l-, or (-).
Right/clockwise rotation = dextrorotatory, dextro-, d- or (+).
Optical rotation is determined with a polarimeter and polarized light source (typically 589 nm) at a standard temp (listed alongside the [alpha] value in the procedure).
Beyond helping to distinguish enantiomers and analysis of asymmetric products, it is of little use when visualizing the actual spatial arrangement of ligands about a chiral center. For this we need to know the abs config about that chiral center.
The more active enantiomorph is referred to as the eutomer.
It's the one you want in your spoon. As in, “You da man, homie, for hookin’ a brotha/cistenon-gender conformer up w/ da good shiz.”
Examples: l-(-)-levorphanol, cis-(+)-3MF, d-(+)-dextromoramide, etc.
Generally, the eutomer is more euphoric. I was trying to make a mathematics joke involving Euler, but I'm shite at maths and nothing comes to mind.
The less active enantiomer is the distomer.
If it's included with the eutomer this is typically acceptable. An equal mole fraction of enantiomers is referred to as a racemate. A Racemic mixture is not necessarily a bad thing. In fact, it makes you a Mix Master Racemate. Or a Mixture of Ceremonies.
If they want to pay out the nose for Lortabby, go to Walgrabby. If they want reasonably priced mu-tuba goodness, they come to mu-mommy. “Muuu!”
Of course if you sell dextromethorphan (DXM) as white bird (“Heron”), you risk getting a Codone stomp. This is a form of levo-larceny and is frowned upon. (cf. “fentafraud”)
Selling a distomer while claiming it is the eutomer is a sign of disrespect.
Hence the dis in distomer.
The *eudismic ratio is the ratio of the activity of the eutomer over distomer.
Most opioid distomers are essentially inert or low-efficacy ligands that interfere very little with eutomer binding. These have little effect on the bioactivity of the Racemate. But sometimes they have antagonistic effects and/or undesired agonism at another receptor. We will cover case studies (some from my gag reel of personal embarrassment) as we continue.
Reversing the configuration of chiral centers will change the direction of optical rotation. Natural l-morphine has the opposite config of the synthetic d-morphine (the distomer) about it's five chiral carbons.
Simpler molecules are easier to visualize.
Switching the config of the chiral center of levo-(-)-(R)-methadone to the (S)-isomer, will give you the antipode with the opposite optical rotation: d-(+)-(S)-methadone (this is the distomer and has 1/40th the potency of the eutomer).
The eudismic ratio, activity/affinity of eutomedistomer, is approx 40:1 in the case of methadone.
We will see how this works in multi-chiral ligands, such a morphinans later on.
Abs config refers to the arrangement of substituents about a chiral center. This is determined spectroscopically via NMR and crystallography, that is, interpreting scatter-patterns formed by beaming X-rays through a high purity crystal (Scat Pat).
In the organic realm, the chiral carbon is king. Inorganicists (Judas Priests) can concern themselves with the supra-ligancy of (hair) metals. We will stick with the simpler tetrahedral axis of Carbonity.
Official IUPAC nomenclature has adopted a handy convention known as CIP Priority Rules. These were developed by the trio Cahn-Ingold-Prelog. When the nobel laureate trio formed a posse, they played around w/ their initials forming ICP. As such, they became the first juggalos to have been honored with a handshake by the Swedish Sovereign. (seriously, CIP rules are important and there’s a whole load of interesting ancillary backstories/anecdotes that are entertaining - ICP = Insane Clown Possee; for anyone who got that joke, I hope you have better taste in music).
The easiest way to pop one’s stereo-cherry is to start with a single point of chirality: one chiral center, one pair of diastereomers. The simplest chiral opioids are those of the acyclic 3,3-diphenylpropylamines. These highly flexible lipophiles pair strong affinity with favorable lipid solubility.
These are simple molecules with a single stereocenter and a high degree of flexibility, allowing their active species to assume different conformations. The eutomers and distomers of the three ligands reviewed have a variety of optical rotations and abs configuration. They help illustrate the difference between the two stereodescriptors.

Simpler Case-Studies: Single Point Chiralities - Methadone/Isomethadone/Moramide


P. Janssen - solid-state X-ray crystallographic diagram of methadone/isomethadone
The MOR-active enantiomer of methadone rotates polarized light to the left and is therefore designated as levo-(-)-(R)-methadone. [Acta Cryst., 11, 724 (1958)]
The config around the asymmetric beta-carbon is assigned (R). Crystallography has revealed that the aminopropyl chain of R-methadone exhibits a gauche conformation. [Cryst. Struct. Comμn. 2, 667 (1973); Acta Chem. Scand., Ser. B 28, 5 (1974)]
The aminopropyl chain of the distomer, dextro-(+)-(S)-methadone, assumes an extended conformation. Despite the extended conformation being unfavorable in the ethylketone series, we will see that this same extended conformation is observed in the more active d-(+)-(S)-moramide (below).
Was is das? We also have the μch more euphorigenic (albeit slightly less analgesic; μch higher therapeutic index) alpha-methyl isomer, known as levo-(-)-(S)-isomethadone. The protonated salt has the same guache conformation as protonated l-(R)-methadone. [J Med Chem, 17, 1037 (1974)].
Despite the shared optical rotation of the iso-/methadone eutomers, their chiral carbons are of opposing abs configs l-(S)-methadone vs. l-(R)-isomethadone. Reversing abs config will only cause a reversal of optical rotation in the same molecule. An (S)-molecule X is not necessarily going to have the same dextro/levo-rotation as its structural isomer, (S)-molecule Y.
The methyl positioned immediately adjacent (alpha) to the bulky 3,3-diphenyl ring system, restricts the low-energy conformations available to isomethadone, resulting in its slightly lower affinity and potency compared to the olympian gymnast methadone. [J Med Chem, 17, 124 (1974); J Pharm Sci, 55, 865 (1966)]
l-(S)-Isomethadone is 40 x more active than its d-(R) antipode. This is 40:1 is a similar eudysmic ratio seen in the methadone series as well.
In case that wasn’t confusing enough, let’s throw in the optically-opposite diastereomers of the moramide persuasion.


3D crystallographic representation of dextromoramide; Tollenaere et al. “Atlas of the Three-Dimensional Structure of Drugs” (1979)
The Moramide eudismic ratio > 10,000. This is the highest recorded ratio in the opiosphere. Featured in a series of opioid diastereomers tested in a MOR affinity study at Janssen involving [3H]-sufentanil displacement, in vitro, rat homogenates, Leysen et al., http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x).
B/c of their drastic difference in affinity, the moramide diastereomers were a popular set of ligands cited by Janssen in his stereospecific investigations within MOR ligands.
In this study, levo-(-)-(R)-moramide had a K(i) > 10,000 and dextro-(+)-(S)-moramide had K(i) of ~ 1.03.
As you will recall, the less active distomer, d-(S)-methadone, assumes an extended aminopropyl conformation. It is l-(R)-methadone that retains most activity and assumes a gauche configuration. In the moramide series, the opposite is true.
The active eutomer d-(S)-moramide assumes an extended confirmation along the morpholino-propyl axis. (angle -159 deg) The moramide eutomer has both the opposite abs config and opposite optical rotation of the R-methadone eutomer.

https://preview.redd.it/jjgnp2jevlx91.png?width=2048&format=png&auto=webp&s=117254960ac40737b25ac9f8f7ebcf73ef7594b7
This is reversed (yet again) in isomethadone, where the l-(S)-isomethadone is the eutomer. The abs config is preserved among the isomethadone-moramide eutomers, but the the optics are not. [Act Chem Scand, Ser B 30, 95 (1976); Bull Soc Chim Fr., 10, 2858 (1965); Act Chem Scand Ser B 29, 22 (1975)]
In the rat hot-plate assay, d-moramide has ~ 20 x potency of morphine (sub-Q). The dur of action (rats, s.c.) is slightly longer than methadone. This is decidedly not so in human clinical practice. d-Moramide is noted for a short dur of action (one-fourth methadone) and a high oral bioavail. In man, however, moramide is far less potent than it is in man. [J Pharm Pharmacol, 9, 381 (1957), Postgrad Med J, 40, 103 (1964)]
I’ve highlighted the discrepancies between rodentine-human potencies in prior monographs. Rats are especially insensitive to the effects of 3,3-diphenylpropylamines. For example, The analgesic ED50 in rats is 10-15 mg/kg for methadone (IV). This would equate to ~ 450 mg dose (IV) or a ~ 900 mg dose (PO) in yours truly.
Even if one had an opioid tolerance capable of handling such ratdiculous doses, the HERG inhibition and other non-specific binding would be more than enough to give a Mini-Thinny mouse some Chipmunky Cheeks (squeaks!). The analgesic ED50 dose in rats is equivalent to > 10 x the (estimated) lethal dose in humans. That's mouserageous!
The d-/l- (+/-) and the (R)/(S) stereodescriptors are independent of one another. The absolute configurations of eutomers and distomers, even those closely related within the same chemical class, do not always agree.
I would throw Fisher’s (now deprecated) “Genealogical System” of (Small Caps) D- and L- into the mix, but juggling two systems is difficult enough, a tri-juggle seems like a jug-to-far.
Let’s Juggalo-along, shall we…

Aminotetralin’ Around


https://preview.redd.it/qmssheswvlx91.png?width=389&format=png&auto=webp&s=c867f8c05af70a2f0d52e0086df1e2a5e835e6d3
While most opioids with a stereo-center will demonstrate stereo-specific binding, there are some interesting exceptions. The above pair of aminotetralin stereo isomers can be thought of as cyclic methadone analogues in which the ethyl ketone moiety has been replaced with a simple methyl group (methadone drawn in the same orientation for comparison). Both of these stereoisomers have the same analgesic ED50, which is on par with pethidine. [J Med Chem, 1973, 16, p 147; p 947]

Novel Ligands 'N Curiosities

This is meant to be a survey of 3D opioid geometries and stereochemistry. But to help wet your novel bespokioid ligand whistle, I will include occasional intermissions highlighting the more unusual and atypical ligands that I’ve encountered during my 14 yrs of exploration. The first is here:
The only “-azocine” that I’ve found worthwhile is the misnomer N-phenethyl 9-(m-hydroxyphenyl) deriv of Anazocine. (despite the shared nomenclature, this has nothing to do with the 6,7-benzomorphans.)(
This is a 3-azabicyclo[3.3.1]nonane (3-ABN), which is akin to a 4-phenyl-4-prodinol with a 3,5-propano bridge gaping the piperidino-divide, m-OH substitution such as that seen in ketobemidone (known to enchance potency in a variety of related compounds; assumed to be analogous to the meta-phenol observed in morphinans) and an unusual 4-methoxy ether at the C(4). The 4-OMe ether is more metabolically stable than 4-propionoxy derivs of prodines (the reversed esters of pethidine). The addition of a 3-Methyl on the piperidine ring stabilizes the 4-propionyl on prodines, making the C(4) less metabolically labile. In a similar manner, the 3,5-propano bridge would be expected to provided steric hindrance and protection against 4-O-demethylation. The m-OH of the phenol can be enhanced further by O-acylation with optimal potency observed by propionyl substitution.
The activity of the N-phenethyl deriv is far less potent in humans than the murine assay suggested (1600 x morphine). The low synthetic yields were the reason that this otherwise worthwhile ligand was only pursued on a single occasion. NIDA dropped interest in using it as a novel opioid receptor probe in the mid 80s. But the Chinese had already been investigating the supra-anazocine derivs since their initial discovery in Japan in the 70s. Much of the Chinese literature of that area remains accessible only at University Archives, which, during my years in grad school, I was able to take full advantage of the opportunity to compile a substantial dossier of literature on this series. In spite of NIDA's unenthusiastic pursuit of a proper SAR elucidation of the series, the Chinese developed over 10,0000 different derivatives and as of today, continue to investigate the series in through the patent literature, hinting that the unique properties of the class may make for marketable research probes that could be commercially useful for opioid research.
The most unique property among some of the optimal Chinese variants is the incredible affinity that these super-agonists have for the MOR. Using CHO assays, the Chinese observed that several derivs strugggled to be displaced by radiolabelled [3H]-lofentanil and [3H]-ohmefentanil. Some required three washings and three successively more cocentrated titrations of [3H]-lofentanil in order for the agonists to be displaced from the receptor. As a full agonist with a Sodium-Index of unity, Lofentanil is unique among agonists, and is believed to form the lowest engergy ligand-receptor binding complex of any kown opioid.
Additional surprises were the fact that nearly all of the Chinese derivs were potent Kappa-antagonists. But that they also had very high therapeutic indices. In several ligands, doses up to 2000 x the therapeutic ED50 analgesic dose were required to depress the rodent's respiration rate by 33%. I'm not sure why they chose to report these ratios in the way they did, except to say that alot of this was done back in the 80s, and many testing and pharmacology standards that we use in the west had not yet been standardized in the Chinese literature.

Substituted Anazocines; the N-phenethyl deriv is one of the more atypical ligands I’ve personally investigated
If you want to get the skinny on this lusty ligand, you’ll have to ball-N-stick around until the end. If you’re ready to get your mind blown, allow me to get down on my kneepads and start the show.

Morphy’s I’d Like to Spoon


14(R) cis-B:C fused morphinans [levorphanol featured] - T-shaped Barrel Plug orientation
This is my favorite graphical representation that helps demonstrate the varied geometries of the many morphinan geometric isomers. The above figure (representing levorphanol) is often called the "T-shaped Barrel Plug" orientation.
The elucidation of the absolute configuration of natural l-morphine allowed for several assumptions to be made about the abs config about the shared analogous stereocenters of other morphinans and 6,7-benzomorphans. These configuration-activity relationships held (mostly) true across the conformationally rigid bonds that compose the morphinans and 6,7-benzomorphans.
The morphinan superfamily consists of three subgenres + closely related 6,7-benzomorphans.
These four polycycles, sometimes referred to as the classical polycyclic opioids, are easily grouped by the number of adjacent fused rings in the system:
Hexacycles: 6,14-endoethano bridged tetrahydrooripavines (Bentley compounds) - semi-synthetic, Diels-Alder adducts of Thebaine [AF Casy, Opioid Analgesics (1986), Chap 4] - KW Bentley discovered these useful Diels-Alder adducts of thebaine and oripavine while working at Reckitt-Benkister and found that the diene system of thebaine was compatible with a plethora of dienophiles.
Pentacycles: 4,5-epoxymorphinans (morphine, oxymorphone) - semi-synthetics, w/ the chracteristic 4,5-epoxymorphinan ring, derived from the three major alkaloids (morphine, codeine, or thebaine) https://sci-hub.se/10.1055/s-2005-862383
Tetracycles: synthetic morphinans (racemorphan, DXM) - fully synthetic, derived from Grewe Cyclization of 1-benzyloctahydroisoquinolines (octabase) [their chemistry along with that of the benzomorphans has been thoroughly reviewed by Schnider et al. in “Organic Chemistry, Vol. 8: Synthetic Analgesics, Part IIa” (1966)]

https://preview.redd.it/mgd59eilzpx91.png?width=1803&format=png&auto=webp&s=360e71e63a0f2a531a277f3770e835a48f1958ae
Tricycles: 5,9-disubstituted 6,7-benzomorphans (phenazocine, pentazocine, metazocine; all clin relevant derivs are of the 5,9-dimethyl variety) - fully synthetic; a variety of synthetic methods are available, but some of the most efficient use a Grewe Cyclization-mimetic strategy [chemistry reviewed by Palmer, Strauss, Chem. Rev. 1977, 77, 1; orig synth by Barltrop, J Chem Soc 1947, 399]

https://preview.redd.it/0cnl7t320qx91.png?width=1672&format=png&auto=webp&s=e0bbaadd74f7b2513b34d92d422f4675f74d4616
While 5,9-disubstituted 6,7-benzomorphans are often treated as a separate class, they are included here. The benzomorphans C5 and C9 correspond to C14 and C13 in the morphinans. These analogous carbons shares the same cis/trans structure-activity relationships that are present in the morphinans.

https://preview.redd.it/okp02ev80qx91.png?width=1312&format=png&auto=webp&s=72440fbcfaa706d1d8c03722652c72e8aba1418a
[The all-carbon stereocenter, corresponding to C13 of the morphinan scaffold (red), is shared among all three morphinan subgenres. The 5,9-disubstituted 6,7-benzomorphans (phenazocine) contain an analogous all carbon center at C5 (same relative position; diff numbering). The unsubst- and 9-mono-substituted benzomorphans lack this feature and are of much lower potency]
The morphinans share a common 5,6,7,8,9,10,13,14-ocatahydrophenanthrene core, as well as much of the same configurational asymmetry (see below). Other than the additional E-ring (formed by the 4,5-ether bridge), the key differences between the three subtypes are variations of the C-ring.

4,5-Epoxymorphinans

Natural l-(-)-Morphine is a T-shaped pentacycle with a central 4-phenylpiperidine (highlighted in bold in figure below) shared with other polycycles and some monocyclic opioids

https://preview.redd.it/33lzzxap0qx91.png?width=2048&format=png&auto=webp&s=75208ebb9eeebb1f96234f63bfb180436415c5aa
Morphine w/ official numbering and rings A-E. The 4-phenylpiperidine core in bold (derived from Rings A + D). The five chiral centers are the bold dots. Note the cis-octalin arrangement of the B:C rings. The C:D rings assume a trans-octahydroisoquinoline arrangement. The cis- and trans-orientation are explained in next section.
The above model is accurate for other 7,8-unsaturated derivs, i.e. codeine, nalbuphine. The partial boat conformation of the C-ring differs from the fully saturated morphinans, (hydromorphone, oxycodone, etc) which have C-rings that conform to the receptor-favored chair conformation.
A brief summary of the boat/chair geometries of the morphinan nucleus is provided in later sections of this monograph.
More in depth discussion of this is avail from J Chem Soc (RSC), 1955, p 3261; Acta Cryst 1962, 15, 326; Chem Pharm Bull, 1964, 12, 104; Eur J Med Chem, 1982, 17, 207, Tetrahedron, 1969, 25, 1851 (trans-B:C fused isomorphine); the latter 3 refs are based on more modern H-NMR, which reached the same conclusions as the earlier crystallography studies).
The five asymmetric carbons of naturally occurring l-(-)-morphine possess the following absolute configurations: C5 (R), C6 (S), C9 (R), C13 (S), C14 (R).
[See the appendix for a brief overview of the CIP Priority Rules that govern these designations; Cahn, Ingold, Prelog - Experientia, 1956, v 12, p 81]
The N-CH3 group is oriented equatorial. The 7,8-double bond causes ring C to assume a half-boat conformation, w/ C6, C7, C8, and C14 lying ~ in the same geometric plane. The three hydrogens at 5-H, 6-H, 14-H are oriented cis, while 9-H is oriented trans. [G. Stork - “The Alkaloids, Vol VI” (1960) p 219; KW Bentley “Chemistry of Morphine Alkaloids” (1954); “The Alkaloids, Vol I” (1956); D. Ginsberg “The Opium Alkaloids” (1962)]

Alternative view of morphine with expanded C-ring shown in the half-boat conformation, w/ the cis-(1,3-diaxial) fused piperidine shown in a perpendicular geometric plane

All of these terms and geometries are reviewed in further detail in later sections.

https://preview.redd.it/mefj5am71qx91.png?width=2048&format=png&auto=webp&s=abac15edcb1201336020410b575196fe55400a27
[natural l-(-)-morphine and its mirror-image enantiomer d-(+)-morphine. Diagram of the basic 3-point receptor model proposed by Beckett & Casy in 1954. The simple Model held true for many decades with little revision and was still being cited in several reviews from the 1980s and 90s. (J Pharm Pharmacol 1954, v 6, p 896; ibid. 1956, v 8, p 848; AF Casy “Opioid Analgesics” (1986) p. 474) (other receptor models developed after the Beckett-Casy postulate include an interesting clay-plaster mold by Martin - https://archives.drugabuse.gov/sites/default/files/monograph49.pdf
The five stereocenters of the inactive d-(+)-morphine are oriented in the exact opposite configuration: 5-(S), 6-(R), 9-(S), 13-(R), 14-(S). [Gates, JACS, 1952, 74, 1109; ibid. 1956, 78, 1380; ibid. 1954, 76, 312]
[Seminal work on morphine stereochem: J Chem Soc, 1955, p 3261; p 3252; Helv Chim Acta 1955, 38, 1847]
Using the 2n formula (n = # chiral centers), 25 = 32 theoretical stereoisomers. Geometric constraints on the morphinan system reduce that number by half (16 isomers). These geometric constraints are due to a number of ring fusions in the morphinan nucleus.
The structure and functional groups attached to the C-ring vary widely among the 4,5,6-ring morphinans. As a result, switching the key ring fusions have a variety of effects on bioactivity and the safety profile of the isomer. Juxtaposition of the cis-B:C rings at the C13-C14 bond results in trans-B:C fused isomorphinans. This is reviewed more thoroughly in later sections.

geometries of cis-B:C fused morphine/levorphanol compared to trans-B:C isolevorphanol
[commentary on Multi-Chiral Molecules (such as morphine) is provided in the comment section]
Despite the hella complicated enantiomeric zoo brought about by five stereocenters, morphine, has rather straightforward chemistry. This is thanks to a series of ring-fusions inherent in the morphinan system.
Get ready for some epic Ring Fusion Morphanity...
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What did flying reptiles evolve from?

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Leeds United's TV schedule includes their Premier League matches on Sky Sports, BT Sport and Amazon Prime, their FA Cup games on the BBC and ITV and their Carabao Cup games on Sky Sports. via
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Be confident.Stand up straight, keep your head and chin up, and look ahead instead of at the ground.Make eye contact with people.Speak slowly and clearly when you talk.Don't fidget.Keep your arms at your sides instead of crossed in front of you.At work, don't be afraid to speak up if you have a good idea. via
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Perbedaan Utama - Anime vs Animasinn Itu perbedaan utama antara anime dan animasi adalah itu anime lebih memperhatikan desain pengaturan dan karakter sedangkan animasi lebih memperhatikan gerakan dan gerakan. via
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Los lenguajes de programación más populares (2021)PYTHON. Es el lenguaje que más popularidad ha ganado últimamente y consiguió llegar a la primera posición por primera vez en octubre de 2021. ... C. ... JAVA. ... C++ ... C# via
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Connecticut state income tax refunds are generally issued within 10-12 weeks from the date that a paper return is received. Tax Refunds for electronically filed, WebFiled or Telefiled returns generally are issued within 4 business days of the receipt of the return. via
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What did flying reptiles evolve from?
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qu'est-ce qu'un robot forex ?

qu'est-ce qu'un robot forex ?
Pourquoi ai-je besoin d'un robot forex ? Probablement, si vous êtes nouveau sur le marché des changes, vous poserez cette question. Peut-être pensez-vous que le cerveau humain peut mieux traiter les informations du graphique et faire de meilleures analyses de change et prendre des décisions sur les orientations possibles du marché. Eh bien… vous vous trompez. Le marché des changes est imprévisible comme la plupart des choses dans nos vies. Si le marché devient prévisible, il cessera d'exister. Alors que pouvons-nous faire? Nous pouvons surveiller et trouver des situations de marché spécifiques après lesquelles quelque chose se passe. Bien sûr, vous ne trouverez jamais un tel cas dans lequel après A suit B avec une probabilité de 100%. Mais vous pouvez en trouver un à 60%. Et cela conduira à développer une stratégie de trading forex et lorsque la stratégie est claire comme du cristal, elle peut être codée dans un conseiller expert. Si nous devons faire une définition de conseiller expert, ce sera — un robot de trading basé sur des statistiques.
Certains conseillers Forex automatisés sont capables de numériser plusieurs graphiques d'une manière que les humains ne peuvent pas physiquement. De plus, les robots sont développés avec des paramètres spécifiques requis pour prendre des décisions de trading. À l'aide des signaux de trading mis en œuvre, ils déterminent quand il est approprié de trader ou, au contraire, d'attendre. Les meilleurs robots de trading Forex offrent des solutions pour trouver des transactions rentables même sur des marchés volatils lorsque la direction de la tendance actuelle n'est pas claire. Les robots Forex automatisés suivent la meilleure tendance pour augmenter les profits et éventuellement éliminer les risques de pertes possibles.
https://preview.redd.it/f2q8fd2njcl71.jpg?width=1920&format=pjpg&auto=webp&s=ba8d51946120cd1d0593bc6281611944ad5d3450

Avantages des robots forex

Le trading automatisé minimise l'impact des émotions associées au processus de trading. En contrôlant leurs émotions, il est généralement plus facile pour les traders de s'en tenir à leur plan de base.
Étant donné que les ordres commerciaux sont exécutés automatiquement dès que les règles de la transaction sont suivies, les commerçants ne pourront pas hésiter ou douter de la transaction.
Le prochain avantage est la possibilité de backtesting. Lors des tests sur des données historiques, des règles de trading sont appliquées aux données de marché historiques pour déterminer la viabilité d'une stratégie. Les traders peuvent essayer ces règles avec forex EA gratuitement et les tester par rapport aux données historiques avant de risquer de l'argent dans le trading en direct.
La discipline de trading est souvent perdue en raison de facteurs émotionnels tels que la peur de perdre ou le désir de tirer un peu plus profit de l'échange. Robot Forex aide à maintenir la discipline car le plan de trading sera suivi exactement.

https://preview.redd.it/k8ktp881lcl71.jpg?width=2121&format=pjpg&auto=webp&s=df4c37fc71cc1ce9c3d329f876a794832a1a8fc1
Vous devez comprendre qu'il n'y a pas de stratégie de trading qui gagne 100% du temps - perdre fait toujours partie du jeu. Cependant, en raison de pertes pouvant causer des dommages psychologiques, un trader qui a perdu deux ou trois trades peut décider de ne pas passer au trade suivant.
La prochaine commande pourrait être réussie, ce qui signifie que le commerçant a déjà gâché les attentes du système. Les systèmes automatisés permettent aux opérateurs d'atteindre la cohérence.
Un autre avantage est la rapidité d'ouverture des commandes. Étant donné que les ordinateurs réagissent instantanément aux conditions changeantes du marché, les systèmes automatisés peuvent générer des commandes si les critères d'échange sont remplis.
Le dernier avantage est que vous pouvez diversifier vos risques. Un robot de trading automatisé permet à l'utilisateur de trader simultanément avec plusieurs comptes ou avec différentes stratégies. Cela peut répartir le risque entre différents instruments, tout en offrant une protection contre la perte du dépôt.
Les traders professionnels utilisent depuis longtemps un tel EA pour Mt4 et Mt5 dans leur travail. Les débutants ne sont pas non plus à la traîne et rejoignent activement ce domaine.
Si vous souhaitez acheter un logiciel forex professionnel, vous pouvez le faire dans ce magasin signal2forex.com
Vous pouvez télécharger gratuitement des robots forex pour certains de nos conseillers afin de voir comment ils fonctionnent dans votre testeur de stratégie avec les paramètres de votre compte.
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TradeGM ajoute des ETF à ses offres de CFD

Le leader du courtage en ligne, TradeGM, a élargi sa déjà large gamme d'offres avec des CFD sur fonds négociés en bourse (ETF).
La société propose la négociation de plus de 200 actifs sous forme de CFD, notamment le forex, les crypto-monnaies, les actions, les indices et les matières premières, et maintenant les ETF.
TradeGM se concentre sur l'offre d'un trading simple, sécurisé et optimisé pour tous, des débutants aux traders avancés.
Désireuse d'offrir aux traders des alternatives améliorées pour la diversification du portefeuille et la gestion des risques, la société a ajouté les CFD ETF à sa gamme déjà étendue d'instruments de trading.
Étant donné que les ETF suivent la performance de plusieurs actifs d'un seul marché ou d'un mélange d'actifs d'un groupe de marchés, ils donnent aux traders une exposition à plusieurs actifs avec un seul investissement, a expliqué TradeGM.

Principales caractéristiques qui rendent les ETF populaires

Les ETF connaissent désormais une demande croissante de la part des traders particuliers et institutionnels en raison de caractéristiques telles que le faible coût de négociation et la diversification facile du portefeuille.
Par exemple, lorsque les commerçants dépensent de l'argent sur des actions, ils doivent réaliser un investissement important pour obtenir des actions d'une seule entreprise. Pour acheter ensuite des actions d'une autre société, ils devront à nouveau effectuer un investissement tout aussi important.
Alors qu'un seul investissement au sein d'un ETF peut offrir une exposition à un segment de marché entier. Cela aide également les commerçants à atténuer les risques.
Si une seule action d'entreprise sous-performe sur le marché, une autre action du panier de l'ETF absorbera le choc.
Lorsque les ETF sont négociés en tant que CFD, les traders n'ont qu'à financer une partie du montant total de la transaction en raison de l'option d'effet de levier.
Les CFD offrent l'avantage supplémentaire de négocier des marchés à la hausse comme à la baisse, car ils seront utilisés pour spéculer sur l'orientation des prix.
Ainsi, lorsque l'on s'attend à ce que les prix augmentent, les commerçants peuvent être longs, tout en devenant courts s'ils s'attendent à ce que les prix baissent à l'avenir.
Une autre caractéristique clé des CFD ETF est que les traders peuvent simplement augmenter leur exposition, sans avoir besoin de faire un investissement plus important.
Ceci est encore une fois facilité par l'effet de levier, où en réalité le commerçant ne finance qu'une partie du montant total de l'investissement, le courtier prêtant le reste.
L'effet de levier n'est qu'une arme à double tranchant et doit vraiment être trouvé avec modération. TradeGM offre un ratio de levier responsable de 1:5 sur les ETF.
La liquidité élevée des ETF est un avantage supplémentaire. Il permet aux traders d'entrer et de sortir des positions à chaque fois qu'ils le souhaitent, car ils seront enclins à localiser facilement une contrepartie à leurs transactions.
De plus, avec une exposition à plusieurs actifs avec un seul investissement, la gestion des risques devient plus facile.

Pourquoi TradeGM est la sélection de prédilection pour les CFD ETF

L'ouverture d'un compte de trading avec un courtier No-Dealing Desk implique que les traders ont l'assurance qu'il n'y a pas de conflit d'intérêts impliquant la maison de courtage et leurs transactions.
TradeGM propose l'utilisation de la liquidité via des fournisseurs de premier plan, ce qui garantit l'exécution des ordres en temps réel et un glissement minimal. Voici quelques-unes des autres caractéristiques qui ont aidé TradeGM à attirer et à fidéliser des dizaines de milliers de clients à travers la planète :

Plateformes de trading robustes

Outre l'utilisation du trading via l'interface Web et les applications mobiles pour Android et iOS, TradeGM propose certaines des plateformes de trading les plus puissantes.
Les traders peuvent choisir entre Metatrader 4 iOS, l'une des plateformes de trading les plus populaires au monde, et GM Trader. GM Trader n'est qu'une plate-forme Web et le dernier ajout à la gamme de plates-formes de négociation de TradeGM.
GM Trader est incroyablement convivial, car il ne nécessite généralement pas que l'utilisateur télécharge ou installe l'application sur son appareil. Il est compatible avec tous les navigateurs et garantit des expériences extrêmement légères et réactives sur n'importe quel appareil.

Comptes multidevises

TradeGM offre une solution simple et pratique pour ouvrir un compte de trading, ainsi que déposer et retirer du compte. Les traders peuvent également choisir d'ouvrir plusieurs comptes et de les financer en utilisant leur sélection de devises, y compris les crypto-monnaies.
Les traders peuvent simplement échanger entre fiat et crypto pour leurs transactions.

Signaux de trading gratuits et actualités quotidiennes

Avec une approche axée sur le client, TradeGM offre les dernières nouvelles du marché et copie les signaux de trading de plusieurs fournisseurs de confiance. Les commerçants peuvent choisir d'obtenir ces mises à jour entièrement sur leur flux TradeGM.
submitted by Indices-stoxx to u/Indices-stoxx [link] [comments]

Existe-t-il un appareil capable de détecter les brouilleurs

📷
Il existe un appareil capable de détecter les brouilleur utilisés pour le vol de véhicules et de marchandises. Les criminels utilisent des brouilleurs pour vaincre les systèmes de navigation et de récupération aéroportés commerciaux et les systèmes de suivi des forces de l'ordre. Drogue / contrebande interdite Souvent, les criminels qui transportent de la drogue et de la contrebande créent des distracteurs pour vaincre le travail de suivi des agents des forces de l'ordre, même s'ils pensent simplement les suivre. C'est un bon outil d'interception qui permet aux policiers de former une raison pour arrêter le véhicule. (Raisons possibles / raisons raisonnables et possibles) Sécurité de la libération conditionnelle Nous pouvons utiliser des brouilleurs pour détecter la libération conditionnelle sur le suivi GPS afin d'éviter de détecter l'entrée dans des zones interdites (terrains de sport, bars). Dépannage de la surveillance / reconnaissance avancée Le détecteur doit faire partie de chaque suite d'installateurs de police pour déterminer s'il y a déjà un brouilleur sur le véhicule ou pour dépanner pourquoi vous ne pouvez pas suivre la cible, éliminant ainsi les méthodes inutiles pour protéger la sécurité de la personne cible. Si la reconnaissance constate que le sujet utilise un brouilleur wifi, d'autres méthodes de surveillance peuvent être planifiées et mises en œuvre.
📷 Les brouilleur de téléphone de signaux sont partout pour vaincre les forces de l'ordre et le suivi électronique. Les criminels utilisent des brouilleurs pour empêcher les appels au 911, prévenir la violence des gangs et dissimuler l'emplacement des maisons protégées contre la drogue. Découvrir activement les appareils d'interférence illégaux Ces dernières années, l'utilisation et la disponibilité de dispositifs de brouillage illégaux ont considérablement augmenté. Ces appareils sont utilisés pour neutraliser les appareils de surveillance et de sécurité, y compris les appareils cellulaires (audio / vidéo), le GPS et le suivi Lojack. Bien que le brouillage du signal lui-même soit illégal dans la plupart des pays / régions, il est toujours difficile de déterminer quand utiliser des brouilleurs. J-ALERT rend la détection et le suivi des brouilleurs faciles, sûrs et rentables. L'analyseur de signaux peut surveiller les fréquences radio cellulaires, le GPS et le Lojack pour déterminer si la cible interfère avec ces signaux. Lorsque l'instrument détecte des interférences dans la bande de fréquence cellulaire, la LED correspondante s'allumera pour indiquer la force du signal reçu (RSSI) du brouilleur et la bande de fréquences interférée. Lorsque la fréquence GPS L1 et la bande cellulaire ou Lojack sont interférées, un graphique à barres s'affiche pour indiquer la force du signal reçu par le brouilleur (RSSI) du brouilleurs GPS, afin qu'il puisse être suivi. S'il interfère avec la bande cellulaire et le GPS L1 en même temps, ou s'il interfère avec Lojack, un bip retentit toutes les 3 secondes. Rappelez à l'opérateur que le brouilleur est utilisé. L'arrière de l'instrument a généralement une prise stéréo avec des contacts N / O et N / C, qui est utilisée pour déclencher un périphérique externe lorsqu'une alarme se produit.
submitted by skylifrshop to u/skylifrshop [link] [comments]

Month 15 - Affiliate/Info Site (Case Study Entry 4) "I f*cking hate Google" to "I f*cking love Google"

Waaaassuupp my just start beauties?
Hope everyone is good. I am currently sitting in awe watching the stock price of GameStop & have a little bit of my own money in it. It's literally like gambling. I used to love gambling so I'm having a whirlwind of a time rn haha! (dw it's money i can lose)
Anyway!!! On with the case study. As always here are last months ones:
Month 12
Month 13
Month 14
Anyways here are the stats:
Mth Articles (total) Pageviews No of Words Affiliate Income (£) Ezoic Income ($) Avg EPMV ($) Total (£)
Oct 2020 45 8475 99,603 316.68 0 0 307.29
Nov 2020 54 40,724 124,284 3865 145.80 9.99 4018.17
Dec 2020 62 20,968 145,215 799.35 112.93 18.54 911.11
Jan 2021 70 21, 743 152,633 746.34 106.79 16.66 824.22
For those of you who dont wanna read, I just started a YouTube where I'll be doing these on camera plus sharing my keyword research methods + anything you want to know.

The Google Update Did Rip My Anus (I Thought I'd Escaped)

So like last month we've seen growth!!
And that may seem just a little ecstatic, but it's because I've had to eat my own words after saying "The Google Update Didn't Rip My Anus (Hooray!)" in the last update. This time around, Google did infact rip my anus.
But it recovered in about 2 weeks to even better positions... I know these are all horrible innuendos and I'm not sorry.
Every part of me wanted to scramble to 'fix' it as best I could those 2 weeks, but I left it alone, stuck to the plan & thanked the affiliate marketing gods it was saved from the burning pits of below top 10 rankings.

My Niche is Profitable But Not Incredibly Profitable

I've learned that the niche I'm currently in is actually pretty hard to earn from. The avg RPM on YouTube is $6/1000 & the affiliate sales aren't as frequent or high in value as say the finance niche or others.
It seems I've put an incredible amount of work into this, but if I'd have chosen a different niche that work would have = more value by now (in my opinion).
So I've basically decided to pretty much outsource all of the content and start a affiliate blogging or finance niche page. Stuff about how you can make money from blogging, stock trading etc. Maybe I'll do this as a YouTube as well, but I'm unsure which I'd rather as of yet.
I quite like just having a site and not having to really show my face. I could outsource the content and put it under my name & no one would know, whereas with YouTube, it always has to be me.

What Changed This Month?

Ezoic Money Machine Didn't Brrr:
I've heard this is pretty normal for most blogs around Jan, but yeah Ezoic dropped heavily for me. Alongside the Google update, it really fucked my chances of getting to my goal of 1000 beautiful Queenie pounds (GBP).
Oh well, next month I think I'm definitely gonna see it get to 1k or at least high 900.
I'm getting about 700-850 visits a day now which is wicked.
Google update, then #1:
Google was a little cunt & threw all his toys out the pram & then tidied them all back up in different positions.
I am grateful for this because, although I didn't see it at the time, I've come back stronger than ever before. I've taken lots of #1 slots for affiliate terms so alllllll good.
It's been interesting to see the shift in amount of money made in each affiliate completely turn on its head. The one I made 90% of my income from most months is now projected to be among the lowest.
Christmas Period Traffic Drop:
So finally the Christmas period traffic has fully gone & I've seen a hit in affiliate earnings on the one I pretty much earned 90% of my income from last month.
It has gone back to its regular 1-5 sales/day, but the commissions I'm getting for these sales are much lower. I am ranking number 1 for quite a few positions containing links to this affiliate, but I guess I'm either not converting for some reason - or the buyer intent isn't really there.
It's a listicle and showcases the best 50 x products - maybe there's too much choice for the buyer? I'm not sure how I'd continue to hold top slot if I cut it down though. I would really appreciate some thoughts here.
I'm trying to rank for a better buyer intent keyword rn with 1k search vol. There's not a lot of competition so I think I can easily take the 3rd slot.
Work Focus Shift:
This month has looked a little different for me work wise. I've now said to myself that I have enough to start outsourcing most of the content on the site, & to step away from it a little bit to start building out other things and diversifying.
If there's one thing I know now - it's that Google's scythe is remorseless. And it can make you wanna be a Chad and punch multiple holes in your dry wall at the flick of a switch. This game is a rollercoaster both rankings and emotion wise lmao.
To combat this I've been focussing a lot on YouTube, & other social media like instagram. I've put out 14 videos this month. And fuck me does video editing suck so much more than writing?!
On Instagram, I've been posting up to 9 times a day, using reels a lot and also posting around 2-3 times on TikTok.
I've grown a lot on IG doing this. I went from 100 - 300 followers this month & only really started 2 weeks ago. I also had a video go viral on TikTok which was good.
Another thing I've done is set up an Etsy shop for one of my IG accounts. I'm happy to share this niche with you bc it's more of an experiment than anything. It's dogs; Labradors to be specific & I'm selling custom shirts to the Instagram followers. I have around 1.15k on there so far & have been growing fairly rapidly.
People love dogs more than people & it's quite crazy the amount of engagement it gets. I can see it being pretty profitable in the future.
New Investment Plans:
The money I make from the site will all go back into content & feeding me. I have plans to get my writer on YouTube with me at the early stages of this channel. I feel like if I involve him at a later date, people will feel cheated. But, if it's 2 people from the start, it will have always been that way.
Maybe that's just me thinking too much, but I sure as hell stopped watching =3 when Ray William Johnson was no longer the main dude. It was shit before, but fuck me did it get shit after he left.
I've also been trading on a Forex demo account for 2 years now & have gotten pretty good at it. I feel like this is another way to expand my income from earning online.
I'm going to get into crypto & forex with some money I won in a competition. I have around $300 to play with, so I'm hoping to get it to $1k investing in DOGE or XRP, & then move that 1k into the more stable currency markets.
Anyway me old fruit...
Hope you enjoyed reading; thanks for reading; and see you in the next episode-sode-sode-sode
*dr dre plays*
Bye!
submitted by hasser964 to juststart [link] [comments]

Le rôle stratégique des drones

Plusieurs fois dans la zone pittoresque, les gens verront certaines personnes utiliser de petits drones pour la photographie aérienne pour enregistrer de beaux paysages, et les nouvelles verront les criminels utiliser des drones pour suivre et capturer secrètement la vie privée, les champs militaires utilisent des drones pour la détection de chemin et Scoutisme, vol de renseignements importants, etc., on peut voir que les drones ont été intégrés dans la vie de nombreuses personnes, alors comment résoudre ces dangers cachés? Les brouilleur drone seront le premier choix.
📷
Que signifie le soi-disant "brouillage" ou "usurpation" d'un drone? Quelle est la différence?
Les pilotes utilisent des télécommandes pour se connecter et contrôler leurs drones. Cependant, ces signaux radio entre la télécommande et le drone peuvent être interrompus. Un terme générique pour une interruption délibérée du signal radio est «brouillage». Mais il existe d'autres moyens de perturber la connexion entre le pilote et son drone, notamment ce que l'on appelle le "spoofing".
Le brouillage envoie intentionnellement un signal d'interférence qui interrompt la connexion radio entre le pilote et le drone. Une fois qu'un signal d'interférence a été envoyé, cela peut forcer le drone à effectuer les opérations suivantes:
Atterrir sur place et arrêter tout mouvement ultérieur
Pour revenir à la position «d'origine», c'est-à-dire le point de départ. De nombreux drones avec GPS disposent de cette fonction dite domestique, qui vise à garantir qu'un drone retourne à son point de départ lorsque le signal radio se coupe.
Lorsqu'elle est effectuée correctement, l'usurpation d'identité permet à un tiers de:
pour reprendre et contrôler le drone
pour télécharger les données et les photos de l'appareil photo
Quels outils sont nécessaires pour le brouillage?
Un brouilleur GPS se compose d'un émetteur qui peut avoir différentes formes et tailles. S'il est dirigé vers un drone, il interrompt les signaux radio et GPS qui le contrôlent. Selon la technologie utilisée, les signaux peuvent être perturbés à quelques centaines de mètres.
Pourquoi quelqu'un devrait-il brouiller un drone?
Les organisations autorisées à utiliser des brouilleurs protègent généralement les zones à haut risque, telles que les bases militaires. Dans une zone de guerre, le service de sécurité militaire peut être en mesure d'arrêter un drone non autorisé avant qu'il ne puisse pénétrer dans une zone protégée et causer des dommages.
Qu'arrive-t-il à un drone coincé?
Le brouillage n'est pas une défense parfaite. Il n'y a aucun moyen de prédire la trajectoire de vol programmée du drone ou de voir s'il peut avoir été programmé pour atteindre une destination prédéfinie même si la liaison radio est perdue. Il peut également ne pas être clair si le drone a à bord une cargaison sensible qui peut être dangereuse si le drone atterrit (casse) ou est arrêté par le personnel de sécurité.
Par rapport aux brouilleur téléphone portable, les drones et le GPS sont généralement effectués en même temps, et tous doivent également bloquer les signaux GPS en même temps, afin que la crise puisse être complètement levée, car les drones ont été perdus.
https://www.jammer-tech.com/homme-nettoie-les-voitures-de-luxe-avec-brouilleur.html
submitted by jammertech to u/jammertech [link] [comments]

Every Legal 4-Letter Word In Scrabble

AAHS AALS ABAC ABAS ABBA ABBE ABBS ABED ABET ABID ABLE ABLY ABOS ABRI ABUT ABYE ABYS ACAI ACCA ACED ACER ACES ACHE ACHY ACID ACME ACNE ACRE ACTA ACTS ACYL ADAW ADDS ADDY ADIT ADOS ADRY ADZE AEON AERO AERY AESC AFAR AFFY AFRO AGAR AGAS AGED AGEE AGEN AGER AGES AGHA AGIN AGIO AGLU AGLY AGMA AGOG AGON AGUE AHED AHEM AHIS AHOY AIAS AIDA AIDE AIDS AIGA AILS AIMS AINE AINS AIRN AIRS AIRT AIRY AITS AITU AJAR AJEE AKAS AKED AKEE AKES AKIN ALAE ALAN ALAP ALAR ALAS ALAY ALBA ALBE ALBS ALCO ALEC ALEE ALEF ALES ALEW ALFA ALFS ALGA ALIF ALIT ALKO ALKY ALLS ALLY ALMA ALME ALMS ALOD ALOE ALOO ALOW ALPS ALSO ALTO ALTS ALUM ALUS AMAH AMAS AMBO AMEN AMES AMIA AMID AMIE AMIN AMIR AMIS AMLA AMMO AMOK AMPS AMUS AMYL ANAL ANAN ANAS ANCE ANDS ANES ANEW ANGA ANIL ANIS ANKH ANNA ANNO ANNS ANOA ANON ANOW ANSA ANTA ANTE ANTI ANTS ANUS APAY APED APER APES APEX APOD APOS APPS APSE APSO APTS AQUA ARAK ARAR ARBA ARBS ARCH ARCO ARCS ARDS AREA ARED AREG ARES ARET AREW ARFS ARGH ARIA ARID ARIL ARIS ARKS ARLE ARMS ARMY ARNA AROW ARPA ARSE ARSY ARTI ARTS ARTY ARUM ARVO ARYL ASAR ASCI ASEA ASHY ASKS ASPS ATAP ATES ATMA ATOC ATOK ATOM ATOP ATUA AUAS AUFS AUKS AULA AULD AUNE AUNT AURA AUTO AVAL AVAS AVEL AVER AVES AVID AVOS AVOW AWAY AWDL AWED AWEE AWES AWFY AWKS AWLS AWNS AWNY AWOL AWRY AXAL AXED AXEL AXES AXIL AXIS AXLE AXON AYAH AYES AYIN AYRE AYUS AZAN AZON AZYM
BAAL BAAS BABA BABE BABU BABY BACH BACK BACS BADE BADS BAEL BAFF BAFT BAGH BAGS BAHT BAHU BAIL BAIT BAJU BAKE BALD BALE BALK BALL BALM BALS BALU BAMS BANC BAND BANE BANG BANI BANK BANS BANT BAPS BAPU BARB BARD BARE BARF BARK BARM BARN BARP BARS BASE BASH BASK BASS BAST BATE BATH BATS BATT BAUD BAUK BAUR BAWD BAWL BAWN BAWR BAYE BAYS BAYT BEAD BEAK BEAM BEAN BEAR BEAT BEAU BECK BEDE BEDS BEDU BEEF BEEN BEEP BEER BEES BEET BEGO BEGS BEIN BELL BELS BELT BEMA BEND BENE BENI BENJ BENS BENT BERE BERG BERK BERM BEST BETA BETE BETH BETS BEVY BEYS BHAI BHAT BHEL BHUT BIAS BIBB BIBS BICE BIDE BIDI BIDS BIEN BIER BIFF BIGA BIGG BIGS BIKE BILE BILK BILL BIMA BIND BINE BING BINK BINS BINT BIOG BIOS BIRD BIRK BIRL BIRO BIRR BISE BISH BISK BIST BITE BITO BITS BITT BIZE BLAB BLAD BLAE BLAG BLAH BLAM BLAT BLAW BLAY BLEB BLED BLEE BLET BLEW BLEY BLIN BLIP BLIT BLOB BLOC BLOG BLOT BLOW BLUB BLUE BLUR BOAB BOAK BOAR BOAS BOAT BOBA BOBS BOCK BODE BODS BODY BOEP BOET BOFF BOGS BOGY BOHO BOHS BOIL BOIS BOKE BOKO BOKS BOLA BOLD BOLE BOLL BOLO BOLT BOMA BOMB BONA BOND BONE BONG BONK BONY BOOB BOOH BOOK BOOL BOOM BOON BOOR BOOS BOOT BOPS BORA BORD BORE BORK BORM BORN BORS BORT BOSH BOSK BOSS BOTA BOTE BOTH BOTS BOTT BOUK BOUN BOUT BOWL BOWR BOWS BOXY BOYF BOYG BOYO BOYS BOZO BRAD BRAE BRAG BRAK BRAN BRAS BRAT BRAW BRAY BRED BREE BREI BREN BRER BREW BREY BRIE BRIG BRIK BRIM BRIN BRIO BRIS BRIT BROD BROG BROO BROS BROW BRRR BRUS BRUT BRUX BUAT BUBA BUBO BUBS BUBU BUCK BUDA BUDI BUDO BUDS BUFF BUFO BUGS BUHL BUHR BUIK BUKE BULB BULK BULL BUMF BUMP BUMS BUNA BUND BUNG BUNK BUNN BUNS BUNT BUOY BURA BURB BURD BURG BURK BURL BURN BURP BURR BURS BURY BUSH BUSK BUSS BUST BUSY BUTE BUTS BUTT BUYS BUZZ BYDE BYES BYKE BYRE BYRL BYTE
CAAS CABA CABS CACA CACK CADE CADI CADS CAFE CAFF CAGE CAGS CAGY CAID CAIN CAKE CAKY CALF CALK CALL CALM CALO CALP CALX CAMA CAME CAMO CAMP CAMS CANE CANG CANN CANS CANT CANY CAPA CAPE CAPH CAPI CAPO CAPS CARB CARD CARE CARK CARL CARN CARP CARR CARS CART CASA CASE CASH CASK CAST CATE CATS CAUF CAUK CAUL CAUM CAUP CAVA CAVE CAVY CAWK CAWS CAYS CEAS CECA CEDE CEDI CEES CEIL CELL CELS CELT CENS CENT CEPE CEPS CERE CERO CERT CESS CETE CHAD CHAI CHAL CHAM CHAO CHAP CHAR CHAS CHAT CHAV CHAW CHAY CHEF CHER CHEW CHEZ CHIA CHIB CHIC CHID CHIK CHIN CHIP CHIS CHIT CHIV CHIZ CHOC CHOG CHON CHOP CHOU CHOW CHUB CHUG CHUM CHUR CHUT CIAO CIDE CIDS CIEL CIGS CILL CINE CION CIRE CIRL CIST CITE CITO CITS CITY CIVE CLAD CLAG CLAM CLAN CLAP CLAT CLAW CLAY CLEF CLEG CLEM CLEW CLIP CLIT CLOD CLOG CLON CLOP CLOT CLOU CLOW CLOY CLUB CLUE COAL COAT COAX COBB COBS COCA COCH COCK COCO CODA CODE CODS COED COFF COFT COGS COHO COIF COIL COIN COIR COIT COKE COKY COLA COLD COLE COLL COLS COLT COLY COMA COMB COME COMM COMP COMS COND CONE CONF CONI CONK CONN CONS CONY COOF COOK COOL COOM COON COOP COOS COOT COPE COPS COPY CORD CORE CORF CORK CORM CORN CORS CORY COSE COSH COSS COST COSY COTE COTH COTS COTT COUP COUR COVE COWK COWL COWP COWS COWY COXA COXY COYS COZE COZY CRAB CRAG CRAM CRAN CRAP CRAW CRAY CRED CREE CREM CREW CRIA CRIB CRIM CRIS CRIT CROC CROG CROP CROW CRUD CRUE CRUS CRUX CUBE CUBS CUDS CUED CUES CUFF CUIF CUIT CUKE CULL CULM CULT CUMS CUNT CUPS CURB CURD CURE CURF CURL CURN CURR CURS CURT CUSH CUSK CUSP CUSS CUTE CUTS CWMS CYAN CYMA CYME CYST CYTE CZAR
DAAL DABS DACE DACK DADA DADO DADS DAES DAFF DAFT DAGO DAGS DAHL DAHS DAIS DAKS DALE DALI DALS DALT DAME DAMN DAMP DAMS DANG DANK DANS DANT DAPS DARB DARE DARG DARI DARK DARN DART DASH DATA DATE DATO DAUB DAUD DAUR DAUT DAVY DAWD DAWK DAWN DAWS DAWT DAYS DAZE DEAD DEAF DEAL DEAN DEAR DEAW DEBE DEBS DEBT DECK DECO DEED DEEK DEEM DEEN DEEP DEER DEES DEET DEEV DEFI DEFO DEFT DEFY DEGS DEGU DEID DEIF DEIL DEKE DELE DELF DELI DELL DELO DELS DELT DEME DEMO DEMY DENE DENI DENS DENT DENY DERE DERM DERN DERO DERV DESI DESK DEUS DEVA DEVS DEWS DEWY DEXY DEYS DHAK DHAL DHOL DHOW DIAL DIBS DICE DICH DICK DICT DIDO DIDY DIEB DIED DIEL DIES DIET DIFF DIFS DIGS DIKA DIKE DILL DIME DIMP DIMS DINE DING DINK DINO DINS DINT DIOL DIPS DIPT DIRE DIRK DIRL DIRT DISA DISC DISH DISK DISS DITA DITE DITS DITT DITZ DIVA DIVE DIVI DIVO DIVS DIXI DIXY DIYA DJIN DOAB DOAT DOBS DOBY DOCK DOCO DOCS DODO DODS DOEK DOEN DOER DOES DOFF DOGE DOGS DOGY DOHS DOIT DOJO DOLE DOLL DOLS DOLT DOME DOMS DOMY DONA DONE DONG DONS DOOB DOOK DOOL DOOM DOON DOOR DOOS DOPA DOPE DOPS DOPY DORB DORE DORK DORM DORP DORR DORS DORT DORY DOSE DOSH DOSS DOST DOTE DOTH DOTS DOTY DOUC DOUK DOUM DOUN DOUP DOUR DOUT DOUX DOVE DOWD DOWF DOWL DOWN DOWP DOWS DOWT DOXY DOYS DOZE DOZY DRAB DRAC DRAD DRAG DRAM DRAP DRAT DRAW DRAY DREE DREG DREK DREW DREY DRIB DRIP DROP DROW DRUB DRUG DRUM DRYS DSOS DUAD DUAL DUAN DUAR DUBS DUCE DUCI DUCK DUCT DUDE DUDS DUED DUEL DUES DUET DUFF DUGS DUIT DUKA DUKE DULE DULL DULY DUMA DUMB DUMP DUNE DUNG DUNK DUNS DUNT DUOS DUPE DUPS DURA DURE DURN DURO DURR DUSH DUSK DUST DUTY DWAM DYAD DYED DYER DYES DYKE DYNE DZHO DZOS
EACH EALE EANS EARD EARL EARN EARS EASE EAST EASY EATH EATS EAUS EAUX EAVE EBBS EBON ECAD ECCE ECCO ECHE ECHO ECHT ECOD ECOS ECRU ECUS EDDO EDDY EDGE EDGY EDHS EDIT EECH EELS EELY EERY EEVN EFFS EFTS EGAD EGAL EGER EGGS EGGY EGIS EGMA EGOS EHED EIDE EIKS EILD EINA EINE EISH EKED EKES EKKA ELAN ELDS ELFS ELHI ELKS ELLS ELMS ELMY ELSE ELTS EMES EMEU EMIC EMIR EMIT EMMA EMMY EMOS EMPT EMUS EMYD EMYS ENDS ENES ENEW ENGS ENOL ENOW ENUF ENVY EOAN EONS EORL EPEE EPHA EPIC EPOS ERAS ERED ERES EREV ERGO ERGS ERHU ERIC ERKS ERNE ERNS EROS ERRS ERST ERUV ESES ESKY ESNE ESPY ESSE ESTS ETAS ETAT ETCH ETEN ETHE ETHS ETIC ETNA ETUI EUGE EUGH EUKS EUOI EURO EVEN EVER EVES EVET EVIL EVOE EVOS EWER EWES EWKS EWTS EXAM EXEC EXED EXES EXIT EXON EXPO EXUL EYAS EYED EYEN EYER EYES EYNE EYOT EYRA EYRE EYRY
FAAN FAAS FABS FACE FACT FADE FADO FADS FADY FAFF FAGS FAHS FAIK FAIL FAIN FAIR FAIX FAKE FALL FALX FAME FAND FANE FANG FANK FANO FANS FARD FARE FARL FARM FARO FARS FART FASH FAST FATE FATS FAUN FAUR FAUT FAUX FAVA FAVE FAWN FAWS FAYS FAZE FEAL FEAR FEAT FECK FEDS FEEB FEED FEEL FEEN FEER FEES FEET FEGS FEHM FEHS FEIS FELL FELT FEME FEMS FEND FENI FENS FENT FEOD FERE FERM FERN FESS FEST FETA FETE FETS FETT FEUD FEUS FEWS FEYS FIAR FIAT FIBS FICE FICO FIDO FIDS FIEF FIER FIFE FIGO FIGS FIKE FIKY FILA FILE FILL FILM FILO FILS FIND FINE FINI FINK FINO FINS FIQH FIRE FIRK FIRM FIRN FIRS FISC FISH FISK FIST FITS FITT FIVE FIXT FIZZ FLAB FLAG FLAK FLAM FLAN FLAP FLAT FLAW FLAX FLAY FLEA FLED FLEE FLEG FLEW FLEX FLEY FLIC FLIM FLIP FLIR FLIT FLIX FLOB FLOC FLOE FLOG FLOP FLOR FLOW FLOX FLUB FLUE FLUS FLUX FOAL FOAM FOBS FOCI FOEN FOES FOGS FOGY FOHN FOID FOIL FOIN FOLD FOLK FOND FONE FONS FONT FOOD FOOL FOOT FOPS FORA FORB FORD FORE FORK FORM FORT FOSS FOUD FOUL FOUR FOUS FOWL FOXY FOYS FOZY FRAB FRAE FRAG FRAP FRAS FRAT FRAU FRAY FREE FRET FRIB FRIG FRIS FRIT FRIZ FROE FROG FROM FROS FROW FRUG FUBS FUCI FUCK FUDS FUEL FUFF FUGS FUGU FUJI FULL FUME FUMS FUMY FUND FUNG FUNK FUNS FURL FURR FURS FURY FUSC FUSE FUSS FUST FUTZ FUZE FUZZ FYCE FYKE FYLE FYRD
GABS GABY GADE GADI GADS GAED GAEN GAES GAFF GAGA GAGE GAGS GAID GAIN GAIR GAIT GAJO GAKS GALA GALE GALL GALS GAMA GAMB GAME GAMP GAMS GAMY GANE GANG GANS GANT GAOL GAPE GAPO GAPS GAPY GARB GARE GARI GARS GART GASH GASP GAST GATE GATH GATS GAUD GAUM GAUN GAUP GAUR GAUS GAVE GAWD GAWK GAWP GAWS GAYS GAZE GAZY GEAL GEAN GEAR GEAT GECK GEDS GEED GEEK GEEP GEES GEEZ GEIT GELD GELS GELT GEMS GENA GENE GENS GENT GENU GEOS GERE GERM GERS GERT GEST GETA GETS GEUM GHAT GHEE GHIS GIBE GIBS GIDS GIED GIEN GIES GIFT GIGA GIGS GILA GILD GILL GILT GIMP GING GINK GINN GINS GIOS GIPS GIRD GIRL GIRN GIRO GIRR GIRT GISM GIST GITE GITS GIVE GIZZ GJUS GLAD GLAM GLED GLEE GLEG GLEI GLEN GLEY GLIA GLIB GLID GLIM GLIT GLOB GLOM GLOP GLOW GLUE GLUG GLUM GLUT GNAR GNAT GNAW GNOW GNUS GOAD GOAF GOAL GOAS GOAT GOBI GOBO GOBS GOBY GODS GOEL GOER GOES GOEY GOFF GOGO GOJI GOLD GOLE GOLF GOLP GONE GONG GONK GONS GOOD GOOF GOOG GOOK GOOL GOON GOOP GOOR GOOS GORA GORE GORI GORM GORP GORY GOSH GOSS GOTH GOUK GOUT GOVS GOWD GOWF GOWK GOWL GOWN GOYS GRAB GRAD GRAM GRAN GRAT GRAV GRAY GREE GREN GREW GREX GREY GRID GRIG GRIM GRIN GRIP GRIS GRIT GROG GROK GROT GROW GRRL GRUB GRUE GRUM GUAN GUAR GUBS GUCK GUDE GUES GUFF GUGA GUID GULA GULE GULF GULL GULP GULS GULY GUMP GUMS GUNG GUNK GUNS GUPS GURL GURN GURS GURU GUSH GUST GUTS GUVS GUYS GYAL GYBE GYMP GYMS GYNY GYPS GYRE GYRI GYRO GYTE GYVE
HAAF HAAR HABU HACK HADE HADJ HADS HAED HAEM HAEN HAES HAET HAFF HAFT HAGG HAGS HAHA HAHS HAIK HAIL HAIN HAIR HAJI HAJJ HAKA HAKE HAKU HALE HALF HALL HALM HALO HALT HAME HAMS HAND HANG HANK HANT HAOS HAPS HAPU HARD HARE HARK HARL HARM HARN HARO HARP HART HASH HASK HASP HASS HAST HATE HATH HATS HAUD HAUF HAUL HAUT HAVE HAWK HAWM HAWS HAYS HAZE HAZY HEAD HEAL HEAP HEAR HEAT HEBE HECH HECK HEED HEEL HEFT HEHS HEID HEIL HEIR HELD HELE HELL HELM HELO HELP HEME HEMP HEMS HEND HENS HENT HEPS HEPT HERB HERD HERE HERL HERM HERN HERO HERS HERY HESP HEST HETE HETH HETS HEWN HEWS HEYS HICK HIDE HIED HIES HIGH HIKE HILA HILD HILI HILL HILT HIMS HIND HING HINS HINT HIOI HIPS HIPT HIRE HISH HISN HISS HIST HITS HIVE HIYA HIZZ HOAR HOAS HOAX HOBO HOBS HOCK HODS HOED HOER HOES HOGG HOGH HOGS HOHA HOHS HOIK HOKA HOKE HOKI HOLD HOLE HOLK HOLM HOLP HOLS HOLT HOLY HOMA HOME HOMO HOMS HOMY HOND HONE HONG HONK HONS HOOD HOOF HOOK HOON HOOP HOOR HOOT HOPE HOPS HORA HORE HORI HORN HORS HOSE HOSS HOST HOTE HOTS HOUF HOUR HOUT HOVE HOWE HOWF HOWK HOWL HOWS HOYA HOYS HUBS HUCK HUED HUER HUES HUFF HUGE HUGS HUGY HUHU HUIA HUIC HUIS HULA HULE HULK HULL HUMA HUMF HUMP HUMS HUNG HUNH HUNK HUNS HUNT HUPS HURL HURT HUSH HUSK HUSO HUSS HUTS HWAN HWYL HYED HYEN HYES HYKE HYLA HYLE HYMN HYPE HYPO HYPS HYTE
IAMB IBEX IBIS ICED ICER ICES ICHS ICKY ICON IDEA IDEE IDEM IDES IDLE IDLY IDOL IDYL IFFY IGAD IGGS IGLU IKAN IKAT IKON ILEA ILEX ILIA ILKA ILKS ILLS ILLY IMAM IMID IMMY IMPI IMPS INBY INCH INFO INGO INGS INIA INKS INKY INLY INNS INRO INTI INTO IONS IOTA IRED IRES IRID IRIS IRKS IRON ISBA ISIT ISLE ISMS ISNA ISOS ITAS ITCH ITEM IURE IWIS IXIA IZAR
JAAP JABS JACK JADE JAFA JAGA JAGG JAGS JAIL JAKE JAKS JAMB JAMS JANE JANN JAPE JAPS JARK JARL JARP JARS JASP JASS JASY JATO JAUK JAUP JAVA JAWS JAXY JAYS JAZY JAZZ JEAN JEAT JEDI JEED JEEL JEEP JEER JEES JEEZ JEFE JEFF JEHU JELL JEON JERK JESS JEST JETE JETS JEUX JEWS JIAO JIBB JIBE JIBS JIFF JIGS JILL JILT JIMP JINK JINN JINS JINX JIRD JISM JIVE JIVY JIZZ JOBE JOBS JOCK JOCO JOES JOEY JOGS JOHN JOIN JOKE JOKY JOLE JOLL JOLS JOLT JOMO JONG JOOK JORS JOSH JOSS JOTA JOTS JOUK JOUR JOWL JOWS JOYS JUBA JUBE JUCO JUDO JUDS JUDY JUGA JUGS JUJU JUKE JUKU JUMP JUNK JUPE JURA JURE JURY JUST JUTE JUTS JUVE JYNX
KAAL KAAS KABS KACK KADE KADI KAED KAES KAFS KAGO KAGU KAID KAIE KAIF KAIK KAIL KAIM KAIN KAIS KAKA KAKI KAKS KALE KALI KAMA KAME KAMI KANA KANE KANG KANS KANT KAON KAPA KAPH KARA KARK KARN KARO KART KATA KATI KATS KAVA KAWA KAWS KAYO KAYS KAZI KBAR KEAS KEBS KECK KEDS KEEF KEEK KEEL KEEN KEEP KEET KEFS KEGS KEIR KEKS KELL KELP KELT KEMB KEMP KENO KENS KENT KEPI KEPS KEPT KERB KERF KERN KERO KESH KEST KETA KETE KETO KETS KEWL KEYS KHAF KHAN KHAT KHET KHIS KHOR KHUD KIBE KICK KIDS KIEF KIER KIEV KIFF KIFS KIKE KILD KILL KILN KILO KILP KILT KINA KIND KINE KING KINK KINO KINS KIPE KIPP KIPS KIRK KIRN KIRS KISH KISS KIST KITE KITH KITS KIVA KIWI KLAP KLIK KNAG KNAP KNAR KNEE KNEW KNIT KNOB KNOP KNOT KNOW KNUB KNUR KNUT KOAN KOAP KOAS KOBO KOBS KOEL KOFF KOHA KOHL KOIS KOJI KOKA KOLA KOLO KOND KONK KONS KOOK KOPH KOPS KORA KORE KORO KORS KORU KOSS KOTO KOWS KRAB KRIS KSAR KUDO KUDU KUEH KUES KUFI KUIA KUKU KULA KUNA KUNE KURI KURU KUTA KUTI KUTU KUZU KVAS KYAK KYAR KYAT KYBO KYES KYLE KYND KYNE KYPE KYTE KYUS
LABS LACE LACK LACS LACY LADE LADS LADY LAER LAGS LAHS LAIC LAID LAIK LAIN LAIR LAKE LAKH LAKY LALL LAMA LAMB LAME LAMP LAMS LANA LAND LANE LANG LANK LANT LANX LAPS LARD LARE LARI LARK LARN LARS LASE LASH LASS LAST LATE LATH LATI LATS LATU LAUD LAUF LAVA LAVE LAVS LAWK LAWN LAWS LAYS LAZE LAZO LAZY LEAD LEAF LEAK LEAL LEAM LEAN LEAP LEAR LEAS LEAT LECH LEED LEEK LEEP LEER LEES LEET LEFT LEGS LEHR LEIR LEIS LEKE LEKS LEKU LEME LEND LENG LENO LENS LENT LEPS LEPT LERE LERP LESS LEST LETS LEUD LEVA LEVE LEVO LEVY LEWD LEYS LEZZ LIAR LIAS LIBS LICE LICH LICK LIDO LIDS LIED LIEF LIEN LIER LIES LIEU LIFE LIFT LIGS LIKE LILL LILO LILT LILY LIMA LIMB LIME LIMN LIMO LIMP LIMY LIND LINE LING LINK LINN LINO LINS LINT LINY LION LIPA LIPE LIPO LIPS LIRA LIRE LIRI LIRK LISK LISP LIST LITE LITH LITS LITU LIVE LOAD LOAF LOAM LOAN LOBE LOBI LOBO LOBS LOCA LOCH LOCI LOCK LOCO LODE LODS LOFT LOGE LOGO LOGS LOGY LOID LOIN LOIR LOKE LOLL LOMA LOME LONE LONG LOOF LOOK LOOM LOON LOOP LOOR LOOS LOOT LOPE LOPS LORD LORE LORN LORY LOSE LOSH LOSS LOST LOTA LOTE LOTH LOTI LOTO LOTS LOUD LOUN LOUP LOUR LOUS LOUT LOVE LOWE LOWN LOWP LOWS LOWT LOYS LUAU LUBE LUCE LUCK LUDE LUDO LUDS LUES LUFF LUGE LUGS LUIT LUKE LULL LULU LUMA LUMP LUMS LUNA LUNE LUNG LUNK LUNT LUNY LURE LURK LURS LUSH LUSK LUST LUTE LUTZ LUVS LUXE LWEI LYAM LYCH LYES LYME LYMS LYNE LYNX LYRA LYRE LYSE LYTE
MAAR MAAS MABE MACE MACH MACK MACS MADE MADS MAES MAGE MAGG MAGI MAGS MAHA MAID MAIK MAIL MAIM MAIN MAIR MAKE MAKI MAKO MAKS MALA MALE MALI MALL MALM MALS MALT MAMA MAMS MANA MAND MANE MANG MANI MANO MANS MANY MAPS MARA MARC MARD MARE MARG MARK MARL MARM MARS MART MARY MASA MASE MASH MASK MASS MAST MASU MATE MATH MATS MATT MATY MAUD MAUL MAUN MAUT MAWK MAWN MAWR MAWS MAXI MAYA MAYO MAYS MAZE MAZY MEAD MEAL MEAN MEAT MECK MEDS MEED MEEK MEER MEES MEET MEFF MEGA MEGS MEIN MELA MELD MELL MELS MELT MEME MEMO MEMS MEND MENE MENG MENO MENT MENU MEOU MEOW MERC MERE MERI MERK MERL MESA MESE MESH MESS META METE METH METS MEUS MEVE MEWL MEWS MEZE MEZZ MHOS MIBS MICA MICE MICH MICK MICO MICS MIDI MIDS MIEN MIFF MIGG MIGS MIHA MIHI MIKE MILD MILE MILF MILK MILL MILO MILS MILT MIME MINA MIND MINE MING MINI MINK MINO MINT MINX MINY MIPS MIRE MIRI MIRK MIRO MIRS MIRV MIRY MISE MISO MISS MIST MITE MITT MITY MIXT MIXY MIZZ MNAS MOAI MOAN MOAS MOAT MOBE MOBS MOBY MOCH MOCK MOCS MODE MODI MODS MOER MOES MOFO MOGS MOHR MOIL MOIT MOJO MOKE MOKI MOKO MOLA MOLD MOLE MOLL MOLS MOLT MOLY MOME MOMI MOMS MONA MONG MONK MONO MONS MONY MOOD MOOI MOOK MOOL MOON MOOP MOOR MOOS MOOT MOPE MOPS MOPY MORA MORE MORN MORS MORT MOSE MOSH MOSK MOSS MOST MOTE MOTH MOTI MOTS MOTT MOTU MOUE MOUP MOUS MOVE MOWA MOWN MOWS MOXA MOYA MOYL MOYS MOZE MOZO MOZZ MUCH MUCK MUDS MUFF MUGG MUGS MUID MUIL MUIR MULE MULL MUMM MUMP MUMS MUMU MUNG MUNI MUNS MUNT MUON MURA MURE MURK MURL MURR MUSE MUSH MUSK MUSO MUSS MUST MUTE MUTI MUTS MUTT MUZZ MWAH MYAL MYCS MYNA MYTH MYXO MZEE
NAAM NAAN NABE NABK NABS NACH NADA NADS NAFF NAGA NAGS NAIF NAIK NAIL NAIN NALA NAME NAMS NAMU NANA NANE NANG NANS NAOI NAOS NAPA NAPE NAPS NARC NARD NARE NARK NARY NATS NAVE NAVY NAYS NAZE NAZI NEAL NEAP NEAR NEAT NEBS NECK NEDS NEED NEEM NEEP NEFS NEGS NEIF NEKS NEMA NEMN NENE NEON NEPS NERD NERK NESH NESS NEST NETE NETS NETT NEUK NEUM NEVE NEVI NEWS NEWT NEXT NGAI NIBS NICE NICK NIDE NIDI NIDS NIED NIEF NIES NIFE NIFF NIGH NILL NILS NIMB NIMS NINE NIPA NIPS NIRL NISH NISI NITE NITS NIXE NIXY NOAH NOBS NOCK NODE NODI NODS NOEL NOES NOGG NOGS NOIL NOIR NOLE NOLL NOLO NOMA NOME NOMS NONA NONE NONG NONI NOOB NOOK NOON NOOP NOPE NORI NORK NORM NOSE NOSH NOSY NOTA NOTE NOTT NOUL NOUN NOUP NOUS NOUT NOVA NOWL NOWN NOWS NOWT NOWY NOYS NUBS NUDE NUFF NUKE NULL NUMB NUNS NURD NURL NURR NURS NUTS NYAS NYED NYES
OAFS OAKS OAKY OARS OARY OAST OATH OATS OATY OBAS OBES OBEY OBIA OBIS OBIT OBOE OBOL OBOS OCAS OCCY OCHE OCTA ODAH ODAL ODAS ODDS ODEA ODES ODIC ODOR ODSO ODYL OFAY OFFS OFFY OGAM OGEE OGLE OGRE OHED OHIA OHMS OIKS OILS OILY OINK OINT OKAS OKAY OKEH OKES OKRA OKTA OLDE OLDS OLDY OLEA OLEO OLES OLID OLIO OLLA OLMS OLPE OMBU OMEN OMER OMIT OMOV ONCE ONER ONES ONIE ONLY ONOS ONST ONTO ONUS ONYX OOFS OOFY OOHS OOMS OONS OONT OOPS OOSE OOSY OOTS OOZE OOZY OPAH OPAL OPED OPEN OPES OPPO OPTS OPUS ORAD ORAL ORBS ORBY ORCA ORCS ORDO ORDS ORES ORFE ORFS ORGY ORLE ORRA ORTS ORYX ORZO OSAR OSES OSSA OTIC OTTO OUCH OUDS OUKS OULD OULK OUMA OUPA OUPH OUPS OURN OURS OUST OUTS OUZO OVAL OVEL OVEN OVER OVUM OWED OWER OWES OWLS OWLY OWNS OWRE OWSE OWTS OXEN OXER OXES OXID OXIM OYER OYES OYEZ PAAL
PAAN PACA PACE PACK PACO PACS PACT PACY PADI PADS PAGE PAHS PAID PAIK PAIL PAIN PAIR PAIS PALE PALL PALM PALP PALS PALY PAMS PAND PANE PANG PANS PANT PAPA PAPE PAPS PARA PARD PARE PARK PARP PARR PARS PART PASE PASH PASS PAST PATE PATH PATS PATU PATY PAUA PAUL PAVE PAVS PAWA PAWK PAWL PAWN PAWS PAYS PEAG PEAK PEAL PEAN PEAR PEAS PEAT PEBA PECH PECK PECS PEDS PEED PEEK PEEL PEEN PEEP PEER PEES PEGH PEGS PEHS PEIN PEKE PELA PELE PELF PELL PELS PELT PEND PENE PENI PENK PENS PENT PEON PEPO PEPS PERE PERI PERK PERM PERN PERP PERT PERV PESO PEST PETS PEWS PFFT PFUI PHAT PHEW PHIS PHIZ PHOH PHON PHOS PHOT PHUT PIAL PIAN PIAS PICA PICE PICK PICS PIED PIER PIES PIET PIGS PIKA PIKE PIKI PILA PILE PILI PILL PILY PIMA PIMP PINA PINE PING PINK PINS PINT PINY PION PIOY PIPA PIPE PIPI PIPS PIPY PIRL PIRN PIRS PISE PISH PISO PISS PITA PITH PITS PITY PIUM PIXY PIZE PLAN PLAP PLAT PLAY PLEA PLEB PLED PLEW PLEX PLIE PLIM PLOD PLOP PLOT PLOW PLOY PLUE PLUG PLUM PLUS POAS POCK POCO PODS POEM POEP POET POGO POGY POIS POKE POKY POLE POLK POLL POLO POLS POLT POLY POME POMO POMP POMS POND PONE PONG PONK PONS PONT PONY POOD POOF POOH POOK POOL POON POOP POOR POOS POOT POPE POPS PORE PORK PORN PORT PORY POSE POSH POSS POST POSY POTE POTS POTT POUF POUK POUR POUT POWN POWS POXY POZZ PRAD PRAM PRAO PRAT PRAU PRAY PREE PREM PREP PREX PREY PREZ PRIG PRIM PROA PROB PROD PROF PROG PROM PROO PROP PROS PROW PRUH PRYS PSIS PSST PTUI PUBE PUBS PUCE PUCK PUDS PUDU PUER PUFF PUGH PUGS PUHA PUIR PUJA PUKA PUKE PUKU PUKY PULA PULE PULI PULK PULL PULP PULS PULU PULY PUMA PUMP PUMY PUNA PUNG PUNK PUNS PUNT PUNY PUPA PUPS PUPU PURE PURI PURL PURR PURS PUSH PUSS PUTS PUTT PUTZ PUYS PYAS PYAT PYES PYET PYIC PYIN PYNE PYOT PYRE PYRO QADI
QAID QATS QINS QOPH QUAD QUAG QUAI QUAT QUAY QUEP QUEY QUID QUIM QUIN QUIP QUIT QUIZ QUOD QUOP
RABI RACA RACE RACH RACK RACY RADE RADS RAFF RAFT RAGA RAGE RAGG RAGI RAGS RAGU RAHS RAIA RAID RAIK RAIL RAIN RAIS RAIT RAJA RAKE RAKI RAKU RALE RAMI RAMP RAMS RANA RAND RANG RANI RANK RANT RAPE RAPS RAPT RARE RARK RASE RASH RASP RAST RATA RATE RATH RATO RATS RATU RAUN RAVE RAVS RAWN RAWS RAYA RAYS RAZE RAZZ READ REAK REAL REAM REAN REAP REAR REBS RECK RECS REDD REDE REDO REDS REED REEF REEK REEL REEN REES REFS REFT REGO REGS REHS REIF REIK REIN REIS REKE RELY REMS REND RENK RENS RENT RENY REOS REPO REPP REPS RESH REST RETE RETS REVS REWS RHEA RHOS RHUS RIAD RIAL RIAS RIBA RIBS RICE RICH RICK RICY RIDE RIDS RIEL RIEM RIFE RIFF RIFS RIFT RIGG RIGS RILE RILL RIMA RIME RIMS RIMU RIMY RIND RINE RING RINK RINS RIOT RIPE RIPP RIPS RIPT RISE RISK RISP RITE RITS RITT RITZ RIVA RIVE RIVO RIZA ROAD ROAM ROAN ROAR ROBE ROBS ROCH ROCK ROCS RODE RODS ROED ROES ROIL ROIN ROJI ROKE ROKS ROKY ROLE ROLF ROLL ROMA ROMP ROMS RONE RONG RONT RONZ ROOD ROOF ROOK ROOM ROON ROOP ROOS ROOT ROPE ROPY RORE RORT RORY ROSE ROST ROSY ROTA ROTE ROTI ROTL ROTO ROTS ROUE ROUL ROUM ROUP ROUT ROUX ROVE ROWS ROWT RUBE RUBS RUBY RUCK RUCS RUDD RUDE RUDS RUED RUER RUES RUFF RUGA RUGS RUIN RUKH RULE RULY RUME RUMP RUMS RUND RUNE RUNG RUNS RUNT RURP RURU RUSA RUSE RUSH RUSK RUST RUTH RUTS RYAL RYAS RYES RYFE RYKE RYND RYOT RYPE
SAAG SABE SABS SACK SACS SADE SADI SADO SADS SAFE SAFT SAGA SAGE SAGO SAGS SAGY SAIC SAID SAIL SAIM SAIN SAIR SAIS SAKE SAKI SALE SALL SALP SALS SALT SAMA SAME SAMP SAMS SAND SANE SANG SANK SANS SANT SAPS SARD SARI SARK SARS SASH SASS SATE SATI SAUL SAUT SAVE SAVS SAWN SAWS SAXE SAYS SCAB SCAD SCAG SCAM SCAN SCAR SCAT SCAW SCOG SCOP SCOT SCOW SCRY SCUD SCUG SCUL SCUM SCUP SCUR SCUT SCYE SEAL SEAM SEAN SEAR SEAS SEAT SECH SECO SECS SECT SEED SEEK SEEL SEEM SEEN SEEP SEER SEES SEGO SEGS SEIF SEIK SEIL SEIR SEIS SEKT SELD SELE SELF SELL SELS SEME SEMI SENA SEND SENE SENS SENT SEPS SEPT SERA SERE SERF SERK SERR SERS SESE SESH SESS SETA SETS SETT SEWN SEWS SEXT SEXY SEYS SHAD SHAG SHAH SHAM SHAN SHAT SHAW SHAY SHEA SHED SHES SHET SHEW SHIM SHIN SHIP SHIR SHIT SHIV SHMO SHOD SHOE SHOG SHOO SHOP SHOT SHOW SHRI SHUL SHUN SHUT SHWA SIAL SIBB SIBS SICE SICH SICK SICS SIDA SIDE SIDH SIEN SIES SIFT SIGH SIGN SIJO SIKA SIKE SILD SILE SILK SILL SILO SILT SIMA SIMI SIMP SIMS SIND SINE SING SINH SINK SINS SIPE SIPS SIRE SIRI SIRS SISS SIST SITE SITH SITS SITZ SIZE SIZY SJOE SKAG SKAS SKAT SKAW SKEE SKEG SKEN SKEO SKEP SKER SKET SKEW SKID SKIM SKIN SKIO SKIP SKIS SKIT SKOL SKRY SKUA SKUG SKYF SKYR SLAB SLAE SLAG SLAM SLAP SLAT SLAW SLAY SLEB SLED SLEE SLEW SLEY SLID SLIM SLIP SLIT SLOB SLOE SLOG SLOP SLOT SLOW SLUB SLUE SLUG SLUM SLUR SLUT SMEE SMEW SMIR SMIT SMOG SMUG SMUR SMUT SNAB SNAG SNAP SNAR SNAW SNEB SNED SNEE SNIB SNIG SNIP SNIT SNOB SNOD SNOG SNOT SNOW SNUB SNUG SNYE SOAK SOAP SOAR SOBA SOBS SOCA SOCK SOCS SODA SODS SOFA SOFT SOGS SOHO SOHS SOIL SOJA SOKE SOLA SOLD SOLE SOLI SOLO SOLS SOMA SOME SOMS SOMY SONE SONG SONS SOOK SOOL SOOM SOON SOOP SOOT SOPH SOPS SORA SORB SORD SORE SORI SORN SORT SOSS SOTH SOTS SOUK SOUL SOUM SOUP SOUR SOUS SOUT SOVS SOWF SOWL SOWM SOWN SOWP SOWS SOYA SOYS SPAE SPAG SPAM SPAN SPAR SPAS SPAT SPAW SPAY SPAZ SPEC SPED SPEK SPET SPEW SPIC SPIE SPIF SPIK SPIM SPIN SPIT SPIV SPOD SPOT SPRY SPUD SPUE SPUG SPUN SPUR SRIS STAB STAG STAP STAR STAT STAW STAY STED STEM STEN STEP STET STEW STEY STIE STIM STIR STOA STOB STOP STOT STOW STUB STUD STUM STUN STYE SUBA SUBS SUCH SUCK SUDD SUDS SUED SUER SUES SUET SUGH SUGO SUGS SUID SUIT SUKH SUKS SULK SULU SUMO SUMP SUMS SUMY SUNG SUNI SUNK SUNN SUNS SUPE SUPS SUQS SURA SURD SURE SURF SUSS SUSU SWAB SWAD SWAG SWAM SWAN SWAP SWAT SWAY SWEE SWEY SWIG SWIM SWIZ SWOB SWOP SWOT SWUM SYBO SYCE SYED SYEN SYES SYKE SYLI SYNC SYND SYNE SYPE SYPH
TAAL TABI TABS TABU TACE TACH TACK TACO TACT TADS TAED TAEL TAES TAGS TAHA TAHR TAIG TAIL TAIN TAIS TAIT TAKA TAKE TAKI TAKS TAKY TALA TALC TALE TALI TALK TALL TAME TAMP TAMS TANA TANE TANG TANH TANK TANS TAOS TAPA TAPE TAPS TAPU TARA TARE TARN TARO TARP TARS TART TASH TASK TASS TATE TATH TATS TATT TATU TAUS TAUT TAVA TAVS TAWA TAWS TAWT TAXA TAXI TAYS TEAD TEAK TEAL TEAM TEAR TEAS TEAT TECH TECS TEDS TEDY TEED TEEK TEEL TEEM TEEN TEER TEES TEFF TEFS TEGG TEGS TEGU TEHR TEIL TEIN TELA TELD TELE TELL TELS TELT TEME TEMP TEMS TEND TENE TENS TENT TEPA TERF TERM TERN TEST TETE TETH TETS TEWS TEXT THAE THAN THAR THAT THAW THEE THEM THEN THEW THEY THIG THIN THIO THIR THIS THON THOU THRO THRU THUD THUG THUS TIAN TIAR TICE TICH TICK TICS TIDE TIDS TIDY TIED TIER TIES TIFF TIFT TIGE TIGS TIKA TIKE TIKI TIKS TILE TILL TILS TILT TIME TINA TIND TINE TING TINK TINS TINT TINY TIPI TIPS TIPT TIRE TIRL TIRO TIRR TITE TITI TITS TIVY TIZZ TOAD TOBY TOCK TOCO TOCS TODS TODY TOEA TOED TOES TOEY TOFF TOFT TOFU TOGA TOGE TOGS TOHO TOIL TOIT TOKE TOKO TOLA TOLD TOLE TOLL TOLT TOLU TOMB TOME TOMO TOMS TONE TONG TONK TONS TONY TOOK TOOL TOOM TOON TOOT TOPE TOPH TOPI TOPO TOPS TORA TORC TORE TORI TORN TORO TORR TORS TORT TORY TOSA TOSE TOSH TOSS TOST TOTE TOTS TOUK TOUN TOUR TOUT TOWN TOWS TOWT TOWY TOYO TOYS TOZE TRAD TRAM TRAP TRAT TRAY TREE TREF TREK TRES TRET TREW TREY TREZ TRIE TRIG TRIM TRIN TRIO TRIP TROD TROG TRON TROP TROT TROW TROY TRUE TRUG TRYE TRYP TSAR TSKS TUAN TUBA TUBE TUBS TUCK TUFA TUFF TUFT TUGS TUIS TULE TUMP TUMS TUNA TUND TUNE TUNG TUNS TUNY TUPS TURD TURF TURK TURM TURN TUSH TUSK TUTS TUTU TUZZ TWAE TWAL TWAS TWAT TWAY TWEE TWIG TWIN TWIT TWOS TYDE TYED TYEE TYER TYES TYGS TYIN TYKE TYMP TYND TYNE TYPE TYPO TYPP TYPY TYRE TYRO TYTE TZAR
UDAL UDON UDOS UEYS UFOS UGHS UGLY UKES ULAN ULES ULEX ULNA ULUS ULVA UMBO UMMA UMPH UMPS UMPY UMRA UMUS UNAI UNAU UNBE UNCE UNCI UNCO UNDE UNDO UNDY UNIS UNIT UNTO UPAS UPBY UPDO UPGO UPON UPSY UPTA URAO URBS URDE URDS URDY UREA URES URGE URIC URNS URPS URSA URUS URVA USED USER USES UTAS UTES UTIS UTUS UVAE UVAS UVEA
VACS VADE VAES VAGI VAGS VAIL VAIN VAIR VALE VALI VAMP VANE VANG VANS VANT VARA VARE VARS VARY VASA VASE VAST VATS VATU VAUS VAUT VAVS VAWS VEAL VEEP VEER VEES VEGA VEGO VEHM VEIL VEIN VELA VELD VELE VELL VENA VEND VENT VERA VERB VERD VERS VERT VERY VEST VETO VETS VEXT VIAE VIAL VIAS VIBE VIBS VICE VIDE VIDS VIED VIER VIES VIEW VIGA VIGS VILD VILE VILL VIMS VINA VINE VINO VINS VINT VINY VIOL VIRE VIRL VISA VISE VITA VITE VIVA VIVE VIVO VIZY VLEI VLOG VOAR VOES VOID VOIP VOLA VOLE VOLK VOLS VOLT VORS VOTE VOWS VRIL VROT VROU VROW VUGG VUGH VUGS VULN VUMS
WAAC WABS WACK WADD WADE WADI WADS WADT WADY WAES WAFF WAFT WAGE WAGS WAID WAIF WAIL WAIN WAIR WAIS WAIT WAKA WAKE WAKF WALD WALE WALI WALK WALL WALY WAME WAND WANE WANG WANK WANS WANT WANY WAPS WAQF WARB WARD WARE WARK WARM WARN WARP WARS WART WARY WASE WASH WASP WAST WATE WATS WATT WAUK WAUL WAUR WAVE WAVY WAWA WAWE WAWL WAWS WAXY WAYS WEAK WEAL WEAN WEAR WEBS WEDS WEED WEEK WEEL WEEM WEEN WEEP WEER WEES WEET WEFT WEID WEIL WEIR WEKA WELD WELK WELL WELS WELT WEMB WEMS WENA WEND WENS WENT WEPT WERE WERO WERT WEST WETA WETS WEXE WEYS WHAE WHAM WHAP WHAT WHEE WHEN WHET WHEW WHEY WHID WHIG WHIM WHIN WHIO WHIP WHIR WHIT WHIZ WHOA WHOM WHOP WHOT WHOW WHUP WHYS WICE WICH WICK WIDE WIEL WIFE WIGS WIKI WILD WILE WILI WILL WILT WILY WIMP WIND WINE WING WINK WINN WINO WINS WINY WIPE WIRE WIRY WISE WISH WISP WISS WIST WITE WITH WITS WIVE WOAD WOCK WOES WOFS WOGS WOKE WOKS WOLD WOLF WOMB WONK WONS WONT WOOD WOOF WOOL WOON WOOS WOOT WOPS WORD WORE WORK WORM WORN WORT WOST WOTS WOVE WOWF WOWS WRAP WREN WRIT WUDS WUDU WULL WUSS WYCH WYES WYLE WYND WYNN WYNS WYTE
XRAY XYST
YAAR YABA YACK YADS YAFF YAGI YAGS YAHS YAKS YALD YALE YAMS YANG YANK YAPP YAPS YARD YARE YARK YARN YARR YATE YAUD YAUP YAWL YAWN YAWP YAWS YAWY YAYS YBET YEAD YEAH YEAN YEAR YEAS YEBO YECH YEDE YEED YEGG YELD YELK YELL YELM YELP YELT YENS YEPS YERD YERK YESK YEST YETI YETT YEUK YEVE YEWS YGOE YIDS YIKE YILL YINS YIPE YIPS YIRD YIRK YIRR YITE YLEM YLKE YMPE YMPT YOBS YOCK YODE YODH YODS YOGA YOGH YOGI YOKE YOKS YOLD YOLK YOMP YOND YONI YONT YOOF YOOP YORE YORK YORP YOUK YOUR YOUS YOWE YOWL YOWS YUAN YUCA YUCH YUCK YUFT YUGA YUGS YUKE YUKO YUKS YUKY YULE YUMP YUNX YUPS YURT YUTZ YUZU YWIS
ZACK ZAGS ZANY ZAPS ZARF ZARI ZATI ZEAL ZEAS ZEBU ZEDS ZEES ZEIN ZEKS ZELS ZEPS ZERK ZERO ZEST ZETA ZEZE ZHOS ZIFF ZIGS ZILA ZILL ZIMB ZINC ZINE ZING ZINS ZIPS ZITE ZITI ZITS ZIZZ ZOBO ZOBU ZOEA ZOIC ZOLS ZONA ZONE ZONK ZOOM ZOON ZOOS ZOOT ZORI ZOUK ZULU ZUPA ZURF ZYGA ZYME ZZZS
submitted by OB8O to 4CHR [link] [comments]

Morphinan History X - Molecusexuality of Opioid Stereochemistry: The Morphinan In the Mirror, Part I - A well cited exploration into the Stereochemistry, Geometry and Sterics of the Opiosphere - by Dμchess Vσn δ + the “Notorious Gibbs Free Energy”

Morphinan History X - Molecusexuality of Opioid Stereochemistry: The Morphinan In the Mirror, Part I - A well cited exploration into the Stereochemistry, Geometry and Sterics of the Opiosphere - by Dμchess Vσn δ + the “Notorious Gibbs Free Energy”
Flaming Spoon Series on Opioidography - Oxycosmopolitan Production

Dμchess Vσn δ + “Notorious Gibbs Free Energy” presents...

Morphinan History X: A High-Heeled “Codone” Stomp of cis/trans-isomerism Drug-Prohibition Bigotry…

Molecusexuality of Opioid Stereochemistry: The Morphinan In the Mirror, Part I

A non-IUPAC approved Molerotic adventure in anthropomorphic Molecular sterics

By:
Edie Norton w/ a Fire Crotch, Sufentstress of the morphinomimetic mattress, the π-pair-o-skinny-jean molecuho, Mini-Thinny Mouse, the RemiFenny Skank, the μ-gμrμ
Dμchess Vσn δ

A well cited exploration into the Stereochemistry, Geometry and Sterics of the Opiosphere

The idea for this post came about as I was working on another post about N-aralkyl substituted morphinans entitled “Tetracycles in Tiaras”. [see u/jtjdp for this post]

In prep’n for that post, I did my typical image hosting on Imgur. The concepts of cis-(1,3-diaxial) piperidine fusion, cis-B:C and trans-C:D ring fusion are important to the morphinan and polycyclic classes. As such, several of my images featured these cis/trans (molecular) orientations quite prominently. It soon earned a slew of downvotes.
I discovered the reason for this lack of opio-enthusiasm when a confused Imgurian left an interesting comment:

“Yo, why do you gotta assign genders?”
Technically these molecusexual orientations were assigned by people. While they aren’t genders as much as geometric orientations, either way, it is forcing nomenclature onto a quantized state of matter. And forced conformations are no a laughing matter.
Forcing a Fetty to be a Frannie, or a Diladdy to be a Maddy, or a Thebby to be Thaddy, is in contravention to the “UN Resolution on Stereochemical Self-Determination.”
A clear cut “heroin rights violation.”
But enantiomers don’t resolve themselves. They need a helping hand.
And that’s how I came up with the idea for Molecusexuality.
Clearly there is a need to explain the long history of the brave pioneering molecules that came out of the cis/trans closet long before the LGBTQ community was even a thing. Nature leads the charge. Humanity eventually followed.
There are some reactions, such as the Knoevenagel (benzaldehyde + nitroalkane), which still remain in the closet, at least until the P2NP nitrostyrene provides the confidence needed to stand proud outside of said closet.
The DEA has been engaging in molecular eugenics for fifty years. They split hairs on matters of cis/trans 4-methylaminorex and countless other higgedy-piggedly matters. Forcing molecules to conform to arbitrary legal codes is as absurd as the concept of prohibition.
Statistically speaking, molecules are braver than man. This, of course, was left out by the mainstream press during Pride Month. I’m here to set the record 109.5 degrees/Tetrahedral.
I’m a medicinal chemist, self-experimentalist, 30-gauge dagger fighta, but when it comes to morphinans and 5,9-dialkyl-6,7-benzomorphans, I’m all about that trans.
In fact, even among the cis-morphinans, i.e. Morphine, cis/trans isomerism is always in play within the the same molecule. The B:C rings exist in cis-fusion while the C:D rings are trans-fused.
The quantum duality of cis-trans ligand-bendery among the morphinans is Quantum Pride. I’ve made few novel discoveries over my career. But I have made many ligands and many of those have graced my spoon.
Of the ~ 25 of these that are of the Opioid variety (especially near and dear to my blood-brain barrier), many have been chiral. As such, they involve a range of stereochemical relationships that are important to their chemical reactivity and bioactivity.
That’s only counting successes. Many were failures. And many of those were due to incorrect stereochemistry. I will share examples with you during the intermissions, entitled: “Epic Failures in Stereoisomerism.”
In humans, mu-stereotypy tends to suppress libido. Making it less sexy. What about other mammals?
While the lab mice are remaining mum as church mice on these topics, their behavior says all we need to know.
Below is a mouse on morphine.

“I’m too sexy for this lab, too sexy for this cage, too sexy for rehab…”
More murine centerfolds found here: https://doi.org/10.1111/j.1476-5381.1960.tb00277.x
This is known as a Straub tail. It has been a hallmark of mu-mediated activity since Straub first noted the phenomena in 1911.
I'm here to make opioids orgasmic and guide you into ligand lust. Welcome to the world of Molecu-sexuality.
This is far from a comprehensive review of the topic. If you seek a deeper dive, I recommend the works of AF Casy, PS Portoghese, NB Eddy, EL May, P Janssen, Leysen, and Van der Eycken.
As with my other chemical musings, these are finger friendly Morph-Dives into the chem. lit. They're abbeaviated, but there's enough page flicking to advise protection. Be sure to wear thimbles, as thumbs are bound to get pricked.

Fundamentals

VOCAB-REHAB
Stereoisomers - isomers with same connectivity; different configuration (arrangement) of substituents
Enantiomers - mirror-image asymmetry; non-superimposable (i.e right-/left-handed morphittens); only differ by the direction (d,l or +,-) of optical rotation
Diastereomers - stereoisomers that are not mirror images; different compounds w/ diff phys properties
Asymmetric Center - tetrahedral carbon w/ sp3 hybridized orbital; capable of σ-bond; (4 different groups attached)
Stereocenter - an atom at which the interchange of two groups gives a stereoisomer
Asymmetric Carbons and cis-trans isomerism are the most common stereocenters
Cis/Trans isomerism - aka: geometric isomerism; applies to orientation of specified groups about a fixed bond, such as a fused heterocyclic morphinan system or an alkene (dbl bond) - cis = same geometric plane; trans = opposite geometric plane; in the morphinan series this refers to fixed constrained alicyclic ring fusions where the amount of rotational freedom is limited
E/Z notation - (E = opposite geometric plane, Z = same geometric plane) Using such notation would make trans-fats become E*-fats* and I don’t believe in furthering the cause of trans-fat bigotry. Thus I will be sticking to the conventional terminology using cis = same side of bond (same geometric plane) and trans to indicate the opposite.
https://i.imgur.com/dNLbPle.png [orbital hybridization chart]
Optically active/Chiral Compound - rotates plane of polarized light in polarimeter (achiral = no rotation) - chiral molec must have an enantiomer
The μ-opioid receptor (MOR) is characterized by stereospecific binding.
There are other features that set the MOR apart from other GPCRs, such as the size of the mouth of its ligand binding pocket (active site), which allows it to fit a wide-range of diverse structures including highly flexible acyclic diphenylheptanones (methadone), the high-mol weight (but mostly planar) etonitazene, the atypical bezitramide, spirodecanones (R5260, R6890), and the most rigid and highly-constrained system in the opiosphere, the 6,14-endo-ethano bridged oripavines. This versatile orifice will be explored later.
Lit Surveys of a number of highly affine ligands with physicochem, IC(50), K(i) data [http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x)] [https://sci-hub.se/10.1016/0014-2999(77)90334-x90334-x)
The crystalline structure of the murine MOR was elucidated in 2011, the same year I finished grad school. There are new discoveries made every day in this area. It can be difficult to keep track of them all, but the link below contains some of the highlights. The molecular dynamics and mechanics of ligand-receptor interactions and the binding modes of the lig-rec complex are important, but are beyond the scope of this monograph.
https://doi.org/10.1038/nature10954

stereospecific binding of bioreceptors
https://sci-hub.se/10.1002/ange.19600721806
Stereospecificity, that is, a preferential affinity for one enantiomer over another, depends upon the ligand’s absolute configuration. That is, the 3D arrangement of substituents as they are configured around a chiral center in real life.
As a matter of convenience and convention, the medical and pharma literature uses optical rotatory stereodescriptors when referring to enantiomers. Examples include d-(+)-amphetamine (Dexedrine) or l-(-)-amphetamine (Lamedrine).
The reason that d-amphetamine is more bioactive than its antipode is due to the receptor-preferred absolute config of its asymmetric carbon, which is configured as (S), which means the substituents about the chiral center (as designed by a convention known as CIP Priority Rules) are oriented in a counterclockwise or left-handed direction.
This is the opposite direction that dextroamphet rotates polarized light. D-(+)-amphet rotates light in a clockwise, (+), or right-handed rotation.
The less active levo-antipode has the (R) abs config, while rotating light to the left or (-).
The optical rotation, in and of itself, does not tell you the abs config about a stereocenter. Nor does the abs config indicate the optical rotation of a compound. Bioreceptors, however, will favor a particular absolute config over another.
Absolute configuration and optical rotation are two separate concepts that are related as they are different ways of classifying stereochemistry, but are not interchangeable. They are measured/determined in different ways.
The most important is absolute configuration. This is the most fundamental property of mol geometry and changes to abs config alters the activity and optical rotation of the molecule. Config is determined with spectroscopy.
Optical rotation is an inherent molecular property that can be measured with polarimetry. A pure optical isomer will have a very specific value. The direction and degree that polarized light is rotated by an enantiomer is an important analytical value found in the Merck Index and the anal. chem. lit. Combined with other data, it can be used to identify and characterize optically active products and even identity unknowns.
Left-handed (like me) or counterclockwise rotation is designed levorotatory, levo-, l-, or (-).
Right/clockwise rotation = dextrorotatory, dextro-, d- or (+).
Optical rotation is determined with a polarimeter and polarized light source (typically 589 nm) at a standard temp (listed alongside the [alpha] value in the procedure).
Beyond helping to distinguish enantiomers and analysis of asymmetric products, it is of little use when visualizing the actual spatial arrangement of ligands about a chiral center. For this we need to know the abs config about that chiral center.
The more active enantiomorph is referred to as the eutomer.
It's the one you want in your spoon. As in, “You da man, homie, for hookin’ a brotha/cistenon-gender conformer up w/ da good shiz.”
Examples: l-(-)-levorphanol, cis-(+)-3MF, d-(+)-dextromoramide, etc.
Generally, the eutomer is more euphoric. I was trying to make a mathematics joke involving Euler, but I'm shite at maths.
The less active enantiomer is the distomer.
If it's included with the eutomer this is typically acceptable. An equal mole fraction of enantiomers is referred to as a racemate. A Racemic mixture is not necessarily a bad thing. In fact, it makes you a Mix Master Racemate. Or a Mixture of Ceremonies.
If they want to pay out the nose for Lortabby, go to Walgrabby. If they want reasonably priced mu-tuba goodness, they come to mu-mommy. “Muuu!”
Of course if you sell dextromethorphan (DXM) as white bird (“Heron”), you risk getting a Codone stomp. This is a form of levo-larceny and is frowned upon. (cf. “fentafraud”)
Selling a distomer while claiming it is the eutomer is a sign of disrespect.
Hence the dis in distomer.
The *eudismic ratio is the ratio of the activity of the eutomer over distomer.
Most opioid distomers are essentially inert or low-efficacy ligands that interfere very little with eutomer binding. These have little effect on the bioactivity of the Racemate. But sometimes they have antagonistic effects and/or undesired agonism at another receptor. We will cover case studies (some from my gag reel of personal embarrassment) as we continue.
Reversing the configuration of chiral centers will change the direction of optical rotation. Natural l-morphine has the opposite config of the synthetic d-morphine (the distomer) about it's five chiral carbons.
Simpler molecules are easier to visualize.
Switching the config of the chiral center of levo-(-)-(R)-methadone to the (S)-isomer, will give you the antipode with the opposite optical rotation: d-(+)-(S)-methadone (this is the distomer and has 1/40th the potency of the eutomer).
The eudismic ratio, activity/affinity of eutomedistomer, is approx 40:1 in the case of methadone.
We will see how this works in multi-chiral ligands, such a morphinans later on.
Abs config refers to the arrangement of substituents about a chiral center. This is determined spectroscopically via NMR and crystallography, that is, interpreting scatter-patterns formed by beaming X-rays through a high purity crystal (Scat Pat).
In the organic realm, the chiral carbon is king. Inorganicists (Judas Priests) can concern themselves with the supra-ligancy of (hair) metals. We will stick with the simpler tetrahedral axis of Carbonity.
Official IUPAC nomenclature has adopted a handy convention known as CIP Priority Rules. These were developed by the trio Cahn-Ingold-Prelog. When the nobel laureate trio formed a posse, they played around w/ their initials forming ICP. As such, they became the juggalos to have been honored with a handshake by the Swedish Sovereign. (seriously, CIP rules are important and there’s a whole load of interesting ancillary backstories/anecdotes that are entertaining).
The easiest way to pop one’s stereo-cherry is to start with a single point of chirality: one chiral center, one pair of diastereomers. The simplest chiral opioids are those of the acyclic 3,3-diphenylpropylamines. These highly flexible lipophiles pair strong affinity with favorable lipid solubility.
These are simple molecules with a single stereocenter and a high degree of flexibility, allowing their active species to assume different conformations. The eutomers and distomers of the three ligands reviewed have a variety of optical rotations and abs configuration. They help illustrate the difference between the two stereodescriptors.

Simpler Case-Studies: Single Point Chiralities - Methadone/Isomethadone/Moramide


Janssen - solid-state crystallographic diagram of methadone/isomethadone
The MOR-active enantiomer of methadone rotates polarized light to the left and is therefore designated as levo-(-)-(R)-methadone. [Acta Cryst., 11, 724 (1958)]
The config around the asymmetric beta-carbon is assigned (R). Crystallography has revealed that the aminopropyl chain of R-methadone exhibits a gauche conformation. [Cryst. Struct. Comμn. 2, 667 (1973); Acta Chem. Scand., Ser. B 28, 5 (1974)]
The aminopropyl chain of the distomer, dextro-(+)-(S)-methadone, assumes an extended conformation. Despite the extended conformation being unfavorable in the ethylketone series, we will see that this same extended conformation is observed in the more active d-(+)-(S)-moramide (below).
Was is das? We also have the μch more euphorigenic (albeit slightly less analgesic; μch higher therapeutic index) alpha-methyl isomer, known as levo-(-)-(S)-isomethadone. The protonated salt has the same guache conformation as protonated l-(R)-methadone. [J Med Chem, 17, 1037 (1974)].
Despite the shared optical rotation of the iso-/methadone eutomers, their chiral carbons are of opposing abs configs l-(S)-methadone vs. l-(R)-isomethadone. Reversing abs config will only cause a reversal of optical rotation in the same molecule. An (S)-molecule X is not necessarily going to have the same dextro/levo-rotation as its structural isomer, (S)-molecule Y.
The methyl positioned immediately adjacent (alpha) to the bulky 3,3-diphenyl ring system, restricts the low-energy conformations available to isomethadone, resulting in its slightly lower affinity and potency compared to the olympian gymnast methadone. [J Med Chem, 17, 124 (1974); J Pharm Sci, 55, 865 (1966)]
l-(S)-Isomethadone is 40 x more active than its d-(R) antipode. This is 40:1 is a similar eudysmic ratio seen in the methadone series as well.
In case that wasn’t confusing enough, let’s throw in the optically-opposite diastereomers of the moramide persuasion.

3D crystallographic representation of dextromoramide, Tollenaere et al. “Atlas of the Three-Dimensional Structure of Drugs” (1979)
The Moramide eudismic ratio > 10,000. This is the highest recorded ratio in the opiosphere. Featured in a series of opioid diastereomers tested in a MOR affinity study at Janssen involving [3H]-sufentanil displacement, in vitro, rat homogenates, Leysen et al., http://sci-hub.se/10.1016/0014-2999(83)90331-x90331-x).
B/c of their drastic difference in affinity, the moramide diastereomers were a popular set of ligands cited by Janssen in his stereospecific investigations within MOR ligands.
In this study, levo-(-)-(R)-moramide had a K(i) > 10,000 and dextro-(+)-(S)-moramide had K(i) of ~ 1.03.
As you will recall, the less active distomer, d-(S)-methadone, assumes an extended aminopropyl conformation. It is l-(R)-methadone that retains most activity and assumes a gauche configuration. In the moramide series, the opposite is true.
The active eutomer d-(S)-moramide assumes an extended confirmation along the morpholino-propyl axis. (angle -159 deg) The moramide eutomer has both the opposite abs config and opposite optical rotation of the R-methadone eutomer.

https://preview.redd.it/kuxj3v91ytc71.jpg?width=2048&format=pjpg&auto=webp&s=af8c566abad46e256c551c66435b2deb46808e98
This is reversed (yet again) in isomethadone, where the l-(S)-isomethadone is the eutomer. The abs config is preserved among the isomethadone-moramide eutomers, but the the optics are not. [Act Chem Scand, Ser B 30, 95 (1976); Bull Soc Chim Fr., 10, 2858 (1965); Act Chem Scand Ser B 29, 22 (1975)]
In the rat hot-plate assay, d-moramide has ~ 20 x potency of morphine (sub-Q). The dur of action (rats, s.c.) is slightly longer than methadone. This is decidedly not so in human clinical practice. d-Moramide is noted for a short dur of action (one-fourth methadone) and a high oral bioavail. In man, however, moramide is far less potent than it is in man. [J Pharm Pharmacol, 9, 381 (1957), Postgrad Med J, 40, 103 (1964)]
I’ve highlighted the discrepancies between rodentine-human potencies in prior monographs. Rats are especially insensitive to the effects of 3,3-diphenylpropylamines. For example, The analgesic ED50 in rats is 10-15 mg/kg for methadone (IV). This would equate to ~ 450 mg dose (IV) or a ~ 900 mg dose (PO) in the lab rat strain known as DuchessVon-Sprauge-Dawley.
Even if one had an opioid tolerance capable of handling such ratdiculous doses, the HERG inhibition and other non-specific binding would be more than enough to give a Mini-Thinny mouse some Chipmunky Cheeks (squeaks!). The analgesic ED50 dose in rats is equivalent to > 10 x the (estimated) lethal dose in humans. That's mouserageous!
The d-/l- (+/-) and the (R)/(S) stereodescriptors are independent of one another. The absolute configurations of eutomers and distomers, even those closely related within the same chemical class, do not always agree.
I would throw Fisher’s (now deprecated) “Genealogical System” of (Small Caps) D- and L- into the mix, but juggling two systems is difficult enough, a tri-juggle seems like a jug-to-far.
Let’s Juggalo-along, shall we…

Aminotetralin’ Around


aminiotetralins
While most opioids with a stereocenter will demonstrate stereospecific binding, there are some interesting exceptions. The above pair of aminotetralin stereoisomers can be thought of as cyclic methadone analogues in which the ethyl ketone moiety has been replaced with a simple methyl group (methadone drawn in the same orientation for comparison). Both of these stereoisomers have the same analgesic ED50, which is on par with pethidine. [J Med Chem, 1973, 16, p 147; p 947]

Novel Ligands 'N Curiosities

This is meant to be a survey of 3D opioid geometries and stereochemistry. But to help wet your novel bespokioid ligand whistle, I will include occasional intermissions highlighting the more unusual and atypical ligands that I’ve encountered during my 14 yrs of exploration. The first is here:
The only “-azocine” that I’ve found worthwhile is the misnomer N-phenethyl 9-(m-hydroxyphenyl) deriv of Anazocine. (despite the shared nomenclature, this has nothing to do with the 6,7-benzomorphans.
This is a 3-azabicyclo[3.3.1]nonane (3-ABN), which is akin to a 4-phenyl-4-prodinol with a 3,5-propano bridge gaping the piperidino-divide, m-OH substitution such as that seen in ketobemidone and an unusual 4-methoxy capping the 4-OH. The activity of the N-phenethyl deriv is far less potent in humans than the murine assay suggested (1600 x morphine). The low synthetic yields were the reason that this otherwise worthwhile ligand was only pursued on a single occasion.

Substituted Anazocines; the N-phenethyl deriv is one of the more atypical ligands I’ve personally investigated
If you want to get the skinny on this lusty ligand, you’ll have to ball-N-stick around until the end. If you’re ready to get your mind blown, allow me to get down on my kneepads and start the show.

Morphy’s I’d Like to Spoon


cis-B:C morphinans [levorphanol featured]
The elucidation of the absolute configuration of natural l-morphine allowed for several assumptions to be made about the abs config about the shared stereocenters of other morphinans and 6,7-benzomorphans. These configuration-activity relationships held (mostly) true across the conformationally rigid bonds that compose the morphinans and 6,7-benzomorphans.
The morphinan superfamily consists of three subgenres + closely related 6,7-benzomorphans.
These four polycycles, sometimes referred to as the classical polycyclic opioids, are easily grouped by the number of adjacent fused rings in the system:
Hexacycles: 6,14-endoethano bridged tetrahydrooripavines (Bentley compounds) - semi-synthetic, Diels-Alder adducts of Thebaine [AF Casy, Opioid Analgesics (1986), Chap 4]
Pentacycles: 4,5-epoxymorphinans (morphine, oxymorphone) - semi-synthetics, derived from the three major alkaloids (morphy, coddy, thebby) https://sci-hub.se/10.1055/s-2005-862383
Tetracycles: morphinans (racemorphan, DXM) - fully synthetic, derived from Grewe Cyclization of 1-benzyloctahydroisoquinolines (octabase) [their chemistry along with that of the benzomorphans has been thoroughly reviewed by Schnider et al. in “Organic Chemistry, Vol. 8: Synthetic Analgesics, Part IIa” (1966)]

https://preview.redd.it/y6p8i5mfytc71.jpg?width=1803&format=pjpg&auto=webp&s=c72e961a9a9723b4136956866d2600c4bd4adc6e
Tricycles: 5,9-disubstituted 6,7-benzomorphans (phenazocine, metazocine; all clin relevant derivs are of the 5,9-dimethyl variety) - fully synthetic; a variety of synthetic methods are available, but some of the most efficient use a Grew Cyclization method [chemistry reviewed by Palmer, Strauss Chem. Rev. 1977, 77, 1; orig synth by Barltrop, J Chem Soc 1947, 399]

https://preview.redd.it/z88xm7vhytc71.jpg?width=1672&format=pjpg&auto=webp&s=85260e1d257066d690e0cda2bbc55f4d37ae5a06
While 5,9-disubstituted 6,7-benzomorphans are often treated as a separate class, they are included here. The benzomorphans C5 and C9 correspond to C14 and C13 in the morphinans. These analogous carbons shares the same cis/trans structure-activity relationships that are present in the morphinans.

https://preview.redd.it/pof8gstkytc71.jpg?width=1312&format=pjpg&auto=webp&s=54115037e207b79aba0b99394067a212ee31798f
[The all-carbon stereocenter, corresponding to C13 of the morphinan scaffold (red), is shared among all three morphinan subgenres. The 5,9-disubstituted 6,7-benzomorphans (phenazocine) contain an analogous all carbon center at C5 (same relative position; diff numbering). The unsubst- and 9-mono-substituted benzomorphans lack this feature and are of much lower potency]
The morphinans share a common 5,6,7,8,9,10,13,14-ocatahydrophenanthrene core, as well as much of the same configurational asymmetry (see below). Other than the additional E-ring (formed by the 4,5-ether bridge), the key differences between the three subtypes are variations of the C-ring.
Natural l-(-)-Morphine is a T-shaped pentacycle with a central 4-phenylpiperidine (highlighted in bold in figure below) shared with other polycycles and some monocyclic opioids.

https://preview.redd.it/txvj7kvoytc71.jpg?width=2048&format=pjpg&auto=webp&s=9719afb7cbfa3ea9e9c211b31a490be3b8020a74
[Morphine w/ official numbering and rings A-E. The 4-phenylpiperidine core in bold (derived from Rings A + D). The five chiral centers are the bold dots. Note the cis-octalin arrangement of the B:C rings. The C:D rings assume a trans-octahydroisoquinoline arrangement. The cis- and trans-orientation are explained in next section.
The above model is accurate for other 7,8-unsaturated derivs, i.e. codeine, nalbuphine. The partial boat conformation of the C-ring differs from the fully saturated morphinans, (hydromorphone, oxycodone, etc) which have C-rings that conform to the receptor-favored chair conformation.
A brief summary of the boat/chair geometries of the morphinan nucleus is provided in later sections of this monograph.
More in depth discussion of this is avail from J Chem Soc (RSC), 1955, p 3261; Acta Cryst 1962, 15, 326; Chem Pharm Bull, 1964, 12, 104; Eur J Med Chem, 1982, 17, 207, Tetrahedron, 1969, 25, 1851 (trans-B:C fused isomorphine); the latter 3 refs are based on more modern H-NMR, which reached the same conclusions as the earlier crystallography studies).
The five asymmetric carbons of naturally occurring l-(-)-morphine possess the following absolute configurations: C5 (R), C6 (S), C9 (R), C13 (S), C14 (R).
[See the appendix for a brief overview of the CIP Priority Rules that govern these designations; Cahn, Ingold, Prelog - Experientia, 1956, v 12, p 81]
The N-CH3 group is oriented equatorial. The 7,8-double bond causes ring C to assume a half-boat conformation, w/ C6, C7, C8, and C14 lying ~ in the same geometric plane. The three hydrogens at 5-H, 6-H, 14-H are oriented cis, while 9-H is oriented trans. [G. Stork - “The Alkaloids, Vol VI” (1960) p 219; KW Bentley “Chemistry of Morphine Alkaloids” (1954); “The Alkaloids, Vol I” (1956); D. Ginsberg “The Opium Alkaloids” (1962)]

Alternative view of morphine with expanded C-ring shown in the half-boat conformation, w/ the cis-(1,3-diaxial) fused piperidine shown in a perpendicular geometric plane
All of these terms and geometries are reviewed in further detail in later sections.

https://preview.redd.it/4sew53fuytc71.jpg?width=2048&format=pjpg&auto=webp&s=df1b0a8e14b6cdba82a9d079c5260dea32385e07
[natural l-(-)-morphine and its mirror-image enantiomer d-(+)-morphine. Diagram of the basic 3-point receptor model proposed by Beckett & Casy in 1954. The simple Model held true for many decades with little revision and was still being cited in several reviews from the 1980s and 90s. (J Pharm Pharmacol 1954, v 6, p 896; ibid. 1956, v 8, p 848; AF Casy “Opioid Analgesics” (1986) p. 474) (other receptor models developed after the Beckett-Casy postulate include an nteresting clay-plaster mold by Martin - https://archives.drugabuse.gov/sites/default/files/monograph49.pdf

The five stereocenters of the inactive d-(+)-morphine are oriented in the exact opposite configuration: 5-(S), 6-(R), 9-(S), 13-(R), 14-(S). [Gates, JACS, 1952, 74, 1109; ibid. 1956, 78, 1380; ibid. 1954, 76, 312]
[Seminal work on morphine stereochem: J Chem Soc, 1955, p 3261; p 3252; Helv Chim Acta 1955, 38, 1847]

Using the 2n formula (n = # chiral centers), 25 = 32 theoretical stereoisomers. Geometric constraints on the morphinan system reduce that number by half (16 isomers). These geometric constraints are due to a number of ring fusions in the morphinan nucleus.
The structure and functional groups attached to the C-ring vary widely among the 4,5,6-ring morphinans. As a result, switching the key ring fusions have a variety of effects on bioactivity and the safety profile of the isomer. Juxtaposition of the cis-B:C rings at the C13-C14 bond results in trans-B:C fused isomorphinans. This is reviewed more thoroughly in later sections.
geometries of cis-B:C fused morphine/levorphanol compared to trans-B:C isolevorphanol
[commentary on Multi-Chiral Molecules (such as morphine) is provided in the comment section]
Despite the hella complicated enantiomeric zoo brought about by five stereocenters, morphine, has rather straightforward chemistry. This is thanks to a series of ring-fusions inherent in the morphinan system
Get ready for some epic Ring Fusion Morphanity...

Cis-(1,3-Diaxial) Fused “IMINO-ETHANO” Inuendo

The most influential steric constant in the entire morphinan superfamily is the cis-(1,3-dixial) fusion of the piperidine ring (ring D).
The centrally located piperidine shares a border with rings B and C. The Piperidine ring contains all three chiral centers in the tetracycles (9C, 13C, 14C).
The fused geometries about the B:C and C:D ring junctions define the stereochem of the series. The one fusion that remains constant in these many stereoisomers is that of the cis-(1,3-diaxial) fusion of the iminoethane system.
The portion of the piperidine system that is mounted above the rest of the molecule is a three member chain (2 carbon + 1 nitrogen; not counting substituents) known as the imino-ethano system.
In other words, the nitrogen-containing half of the piperidine is mounted above the morphinan system in a geometric plane that is roughly perpendicular to the rest of the molecule.

edge-on view of B-ring in Dextrorphan; the imino-ethano fusion is the same in all stereoisomers of the morphinan system

As you can see in the above figure, the piperidine D-ring shares C9, C13, C14 with other rings. The iminoethane portion is anchored to C9 and C13.
When we refer to the iminoethano system being locked in a cis-(1,3-diaxial) orientation we are referring to the anchor points at C9 (position 1) and C13 (position 3). The cis simply means both legs of the iminoethane system are oriented in the same Geometric plane.
This is a fancy-pants mack-momademic way of saying that this D-ring is carried at a high center of gravity on the bosom of morphy. In others words, morphy has a very ample bosom. A pi-pair-o-D’s. A 44D-(ring) bust. Morphinan is top heavy*.
Morphy is the Dolly Parton of the polycycles. Dolly = D-ring, Parton = Piperidine. Hence the nomenclature.
The same applies to Morphy's awkward teenage daughter: Lil’ Thebby. Her parents call her Thebitha. We know her as Thebaine.
Lil’ Thebby inherited the 3-methoxy from her father (*Coddy). She has her father's large feet. (Don't make fun; she's already self conscious)
Thebby inherited the ample D-ring of her mother, Morphy. This leaves Thebby awkward and top heavy. Despite the added methoxy shoe size, she is still learning the quantum balancing act.
Her C-ring has yet to fully fill-out. Her 6,7,8,14-diene *derriere is rather flat. Her pi-orbital pair of skinny jeans still fit, but the diene system makes her C-ring very nearly planar; that is, nearly as flat as her Aromatic A-ring.
If the A and C rings were her thighs, she has one 2D flat thigh, another looking like it's been half run over by a truck, her leg brace (the 4,5 epoxy bridge) attaches her flattened thighs and makes it so she can only waddle. Quack! At least that’s what the fentalogues say at school.
One moleculestor who has taken note of that Lil’ Thebby Snack, is the rough n tumble dienophile, known as Diels-Alder. He’s in the adduction business. He’s determined to help fill-out the less defined traits of our dear Thebby.
The nature of the double D-ring mounted out front serves as steric hindrance to reactive groups, such as the dienophile, seeking front-side access to the diene system. The planarity (flat) of the C-ring provides another side of attack.
The orientation of all this piperi-cleavage weighs down the more flexible non-aromatic rings, causing the frontwards heroin hunch. This bent-over Thebby Snack presents an ideal target for the adduct-friendly dieno-who-will-defile.
As a result, the Endonk-Ethonk bridge is formed across the rear face of the C-ring (the side opposite that of the piperidine). Crystallography has confirmed that the endo-etheno bridge gapes across the opposite side of the C-ring from C6 to C14. Hence 6,14-endo-etheno.
Despite the embellishment this is a fairly accurate description of the steric factors that come into play during the dieno-debauchery of the Diels-Alder rxn. The cis-(1,3-diaxial) fusion and position of the D-ring exerts a steric influence on the geometries of derivs, esp those of thebaine.
This is hardly a storybook molemance nor is it an acyclic contortion fest from the pages of the Carfent Sutra. This is a C-ring Carfeeper. A back-door-dieneoxplorer by Remi Jeremy.
Perhaps I’m somewhat biased b/c of my own 32Aromatics. I’m not one to knock a pi before I try, so perhaps I’m being bit too harsh on this Ciramadoll.
Regardless of the manner in which “Thebby Got Her endo-eThighno Gap”, the molecular end game is the same. The result is a thing of beauty...

https://preview.redd.it/kmdg0puwztc71.jpg?width=1000&format=pjpg&auto=webp&s=9f0b449adce91835f142301bd05103547628bbbb
[6,14-endoetheno-tetrahydrothebaine: iminoethane system projecting towards viewer; 6,14-endoetheno bridge projecting away from viewer; hanging off the C-ring like a endonk-ethonk]
This 6,14 endo geometry is ideally paired with a C-7 lipophilic chain that has a 19-tert-OH oriented in (R)-config (eutomer). The (S)-config is the distomer.

https://preview.redd.it/hpkynna10uc71.jpg?width=2048&format=pjpg&auto=webp&s=dffe68edab89229777d05881f9c32293f7974007
[(S)- and (R)-config; shows the Hydrogen bond formed between the 6-OCH3 and the 19-OH; forming the “russian nesting doll” situation in which bonds of all sorts wrap up the C-ring in the bridged derivs]
Wonderful reviews on the chemistry of the bridged oripavines have been prep’d by Bentley, “The Alkaloids, Vol. 13” p. 1 (1971); Ann Rev Pharmacol Toxicol, 1971, 11, 241. And others: J Med Chem, 1973, 16, 9; Adv Biochem Psychopharmacol, 1974, 8, 124; Prog Drug Res, 1978, 22, 149]

https://preview.redd.it/wnd7q4n50uc71.jpg?width=828&format=pjpg&auto=webp&s=0455ef877d4abf9e36c0958d933e43f2834cb144
[a view of the geometries about alt axis of the antags of the 4,5,6-ringed morphinans; changes in the C-ring have drastic consequences for geometries]
As we just reviewed, the addition of the dienophile to thebaine is restricted to the exposed face of the C-ring, which gives us the 6,14-endoetheno derivs. Here, endo implies that the 6,14-bridge lies in a config opposite to the 14-H and the 6-methoxy. The literature designates this orientation as alpha.
https://i.imgur.com/0vNCQ9r.jpg
[rel stereochem of bridged thebaines with numbering]
The Diels-Alder addition of dienophiles may occur in such a way as to give C7 Beta-epimers (seen in diagram below). The different epimers could have formed w/ equal likelihood. But stereochem control of Diels-Alder addition results in products with C7-alpha geometry and very minute qty of the opposite C7-beta adduct.

[alpha, beta epimers at both C7 and C8
Without taking into account the greater electronic-steric control of the system, it appears that the use of asymmetric dienophiles (alkyl vinyl ketones, acrylonitriles, acrylic esters, etc) could result in both C7 and C8 substituted adducts. The electro-steric effects of the system gave only C7-substituted products. [JACS, 1967, 89, 3267; Nature, 1965, 206, 102]
A more recent review on oripavine chemistry is avail at http://dx.doi.org/10.4236/abb.2014.58084

PART II/COMMENTS

The comments section will have additional images that reddit did not allow me to post due to their system limits. The Comments will also feature a few of my opinions and commentary that are parenthetical deviations from the main narrative of the stereochem lecture.
The next part (PART II) will delve into the exciting world of the Cis and Trans-B:C ring fusions in the cis-morphinans and trans-isomorphinans, stereoisomerism about the 14-carbon, that is,14(R) and 14(S) isomers, the world of chair and boat conformational/geometric isomerism, and their effects on biological activity.
Future updates to this series will be posted at AskChemistry
The #1 rule here at AskChemistry is absolutely NO DOXXING of Redditors. Users are entitled to their anonymity and the fundamental right to privacy is respected. We tolerate many different views and a differing of opinions are the spice of life, but anyone attempting to DOXX, that this, making otherwise private information about another redditor public, will be censored and repeated violations will result in bans and reporting to admins.
Communications of a general nature can be directed to my reddit handle u/jtjdp
Communications of more private/confidential nature should be directed to my Wickr username: DuchessVonD
Please use Honeycombing sense when posting and communicating.
submitted by jtjdp to AskChemistry [link] [comments]

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