What makes an opioid an opioid?

[Trabbamab]

This is something that has bugged me for years. I have tried looking for resources that would give some kind of explanation but they are either way too deep for me to understand (written for pharmacologists) or they focus more on explaining the different receptors, etc. Maybe I am not asking the question in the right way.

For most drugs, it seems that there is some kind of similarity in the molecule among drugs of a similar class. Worlds of drugs are built off of the phenethylamine molecule. But then you start looking at opioid molecules and see something like heroin and also something like fentanyl. How do these drugs have such similar effects when they look, to me, like they are 100% unrelated?

Are there any tell-tale signs from the molecule that would tip someone off that a particular substance could affect opioid receptors? Or are these things simply found through experimentation and then mutating known molecules? Does it take years of study and a deep knowledge to look at a potential novel opioid molecule and see it for what it could potentially be?

 

[Hodor]

Comparing heroin and fentanyl is kind of like comparing 25I-NBOMe and LSD and concluding there are no structural similarities between psychedelics.

Heroin belongs to the morphinan class of opioids, just like morphine (which it is a pro-drug for). Codeine, Hydrocodone, Oxycodone, Oxymorphone, Hydromorphone, Etorphine, Desomorphine... all of these will produce strong analgesia via mu-receptor agonism.
Likewise, when you look at the first synthetic opioid, pethidine, and compare it to, say, tilidine, it seems unsurprising that both are potent opioids. It also becomes easier to see how Paul Janssen could arrive at the discovery of other opioids like diphenoxylate, piritramide and eventually fentanyl.

And yes, "no duh" you will find "worlds of drugs" built off the phenylethylamine molecule . That's because PEA is an extremely simple backbone - as such, it is also impossible to predict what a compound based on this structure will do - you might get a nasal decongestant (beta-hydroxy, alpha,N-dimethyl-PEA aka pseudoephedrine), a dopamine releasing agent (alpha-methyl-PEA aka amphetamine), a hallucinogen (3,4,5-trimethoxy-PEA aka mescaline) and many others. Only once you narrow down the structure a bit you can predict what a phenylethylamine-class drug will do (ex.: 2,5-dimethoxy-4-bromo-PEA aka "2C-B" can be expected to have similar effects to other 2,5-dimethoxy-4-X-PEA's).

 

[clubcard]

Use Chemoffice. The 5 moieties are:

-2 Aromatic systems
-Basic nitrogen
-2 hydrogen-bond acceptors

In specific spacial relationship. You will find that most do not have all but the more they have, the more active they are. That is why the pyrrolidone analogue of Viminol, trans BDPC, W18 and OHMEfentanyl overlay so closely in their active conformation. Finding the active conformation poses a problem when it's a near-minimum rather than minimum energy conformation that is active. I have always told sub-graduates to use 7-PET ((2R)-2-((4R,7S,7aR,12bS,14R)-7,9-dimethoxy-3-methyl-1,2,3,4,7,7a-hexahydro-7,4a-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-14-yl)-4-phenylbutan-2-ol) as the prototype.

Hodor is right. For both the PEA and IEA classes of 5HT2a ligand, I suggest LSD as the prototype. It is plain that the amide is space-filling and it is the hydrogen bond acceptor is a specific spacial position. That what the German researcher proved. The NBomE (I forget the naming) isn't rigid but you can map the indole, basic nitrogen and O: perfectly. All classes have members which contain enantiomers and tilidine is one of the most interesting compounds I have come across. One of the trans isomers (cis isomers are removed) overlays the aromatic, basic amine and hydrogen bond acceptor of morphine and the other overlays the PEAs. Dopamine release is part of it's activity and it's clear if you look at the reversed isomer (look on wiki). I contacted Dr Derek. P. Reynolds and he was rather pleased to discover that the 'inactive' isomer of the monomethyl amine (norisotilidine?) actually overlays cypenamine. I can also confirm that it follows the trend of the reversed esters. The patent doesn't have a good route to make the active metabolite but a paper printed in the last 3 months is convenient for the alkene->N-methyl aziridine->N-monomethyl aminoester (bis diyl in action). Before that, you had to use one of the Sharpless Hydroxyamination methods which as I'm sure people will realize, isn't of practical value so it isn't a synthesis.

 

[sekio]

That is why the pyrrolidone analogue of Viminol, trans BDPC, W18 and OHMEfentanyl overlay so closely in their active conformation.

Hasn't W-18 been proven to not be an opioid?

 

[Trabbamab]

Thank you very much for the info. And yes, phenethylamine was not the best example. As you can probably easily tell, this is not my field of study (that would be computer science). And thank you, Clubcard, as I think that is probably what I am looking for!

 

[Hodor]

Thank you very much for the info. And yes, phenethylamine was not the best example. As you can probably easily tell, this is not my field of study (that would be computer science). And thank you, Clubcard, as I think that is probably what I am looking for!

Another interesting factor, IMO, is the overlap between some of the synthetic opioids and monoamine reuptake inhibitors and/or NMDA antagonists.

As clubcard already pointed out, tilidine?s metabolites can act as dopamine reuptake inhibitors, contributing to its analgesic effect while also significantly increasing its abuse potential; same with meperidine. Tramadol?s SNRI effect likewise contributes to its efficacy as a painkiller, but without a major increase in abuse liability; unfortunately, those who *do* end up abusing it can easily run the risk of seizures/serotonin syndrome. Let?s also not forget venlafaxine, a non-opioid SNRI with a structure not too far removed from tramadol.

Lefetamine, a diarylethylamine, is another example of an opioid doubling as a noradrenergic stimulant. Replace its two N-methyl groups with a single N-ethyl though, and you?ve got Ephenidine, a popular grey-market dissociative, especially in markets where the more potent arylcyclohexamine dissos are unavailable.

 

[klfiend]

Any idea what extending one or both of the methyl groups on lefetamine would do?

 

[clubcard]

Hasn't W-18 been proven to not be an opioid?

Well It overlays the other compounds I mentioned exactly - or at least Chemoffice and Discovery Studio did.

Are you sure it isn't because you need to stick to the original route or, with it being semi-rigid, you end up with the inactive conformer? A surprise to me because it ticks every box. Try it in Chemoffice - minimum-energy state relies on original state - no WAY will the body provide the energy to change conformation. I DID have to meddle in Chemoffice to ensure the trans isomer.

 

[sekio]

W-18 may overlay fentanyl in some conformation, but it still lacks affinity for mu-opioid receptors in vitro (presumably in vivo too). In fact the whole sordid story of W-18 is a classic case of media escalating what should have been a non-issue into a Big Fucking Deal, all based upon a single paper indicating that W-18 may be a potent analgesic of unknown mechanism.

 

[Kdem]

I guess binding to the opioid receptors is the key ... whatever the chemical structure may be.

 

[Pickledlemons]

Hasn't W-18 been proven to not be an opioid?

Thats correct. but it still produces euphoria and analgesia... its just that the mechanism is unknown. I think....

 

[clubcard]

W-18 may overlay fentanyl in some conformation, but it still lacks affinity for mu-opioid receptors in vitro (presumably in vivo too). In fact the whole sordid story of W-18 is a classic case of media escalating what should have been a non-issue into a Big Fucking Deal, all based upon a single paper indicating that W-18 may be a potent analgesic of unknown mechanism.

I bow to your superior knowledge. I am surprised, but now I can at least narrow down the QSAR of the mu receptor. I remember that it was analgesic, but delta agonists feel weird and kappa agonists do no bear thinking about ;-)

 

[sekio]

All I know about W18 is what I read in the literature

Apparently the only binding site that W-18 has been proven to bind to is the peripheral benzodiazepine receptor (note: not the same as the GABA receptor where benzos bind), and possibly hERG.

As far as euphoric potential, I doubt it actually produces dependence or conditioned place preference like opioids do. Remember the whole media frenzy was based on 1 paper where they were using it to test analgesia by the rat on a hot plate method - testing for analgesic potential and not specifically opioid activity. So as far as I am convinced W-18 should be just as "fun" as ibuprofen.

 

[clubcard]

At the risk of being totally wrong again, the book 'Opiates' by R.Lenz et al gives a potency figure of 2240 pethidine for 1-phenyl-8-(1-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one. As you can see, it's a semi-rigid fentanyl analogue. Nobody is going to be making THAT, I don't think. It was discovered by Janssen when looking for neuroleptics and fluspirilene (Imap) was said drug. Likewise pimozide (Orap) lead to the discovery of bezitramide. I think it's OK to mention these because nobody is ever going to make them. Placing a phenyl onto the 4 position of phenapromide (and propiram) makes an exact fentanyl overlay but that chiral methyl - well, just think about it. No WAY will even the Chinese go there. I guess chiral viminol analogues are possible but not potent - it amazes me. People only go for the super-potent. Sure, there are a lot still not known outside the Eunoia disc but the DEA can't put a dent into fentanyl so I guess Grisham's law applies - 'potent but dangerous opioids push less potent but safer opioids out of the system'. I am paraphrasing the words but you know what I mean. If people cannot safely eyeball it - it's inherently dangerous. Given a free market, dipipanone, levorphanol and norisotilidine (maybe with dextromoramide and ketobemidone) would be the choices of the people..... But who can buy a house from a single dipipanone deal?

I digress. The greed sickens me. Who enjoys money earned by killing people? Even if you didn't know them, how can you NOT think about all of those destroyed lives. Long live dihydrocodeine - enough so I can walk, not so much I cannot think (and worse than usual).

 

[George27]

How do these drugs have such similar effects when they look, to me, like they are 100% unrelated?

Are there any tell-tale signs from the molecule that would tip someone off that a particular substance could affect opioid receptors?

The morphine rule:

http://derekwmeyer.blogspot.it/2011/02/winner-junkies-and-patients-have-spoken.html

 

[clubcard]

The statement on the structure is a guide; it stopped being a 'law' in about 1973 when whole groups that didn't follow that set turned up. It is useful for subgrads to use, but Lednicer and many others broke away from that belief.