Teaching the theory (and conjectures) of (Semi)synthetic opiate design

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Let us begin with the prototype and most basic touch-stone for those developing novel opioids (definition - synthetic or semisynthetic derivatives of morphine).

I REALIZE that above giving names to the ring structures, this looks pretty dumb but trust me, I have a LOT to impart including stuff I have no answer to and so YOUR voices are important.

I've already built lesson II but I want to know people are OK with being presented with stuff they have no RATIONAL responses to because, as a medicinal chemist noted 'The QSAR of opioids it like 'Alice through the Looking Glass' and that's the guy who invented MXE put it, so he isn't an idiot... there are MANY things we just don't know.

And a m-phenol function is the MOST tricky. If you didn't know, it isn't possible for an opiate ligand to be an ANTAGONIST without a m-OH,,, which is a simple rule but wasn't recognized until the late 1950s which is why 3-methyl ketobemidone (some 5.5 x morphine in potency) was never discovered at the time. Otto Eisleb (discoverer of MPPP, ketobemidone, prodine and so on) never spotted the fact. His job was to use the limited technology to produce the most potent phenylpiperidine opioid possible so MPPP, prodine and ketobemidine were his domain... but only 30 years later did someone work out that allylprodine, via careful testing. proved to be x23 M in potency. Adjust for MW and it's x8 M in potency.

I will attempt to provide facts and ask for people to suggest that which is not known. I mean, science not looking TOO hard. The KEY is, you know more than you think you do.

So we will explore ALL opioids. So step one is those strange names....

But let me tell you the absolute truth- ALL of you are more than able of understanding and designing novel opioids. It feels to me that it's almost the mystery of opioids that makes it feel as if non-chemists could NOT POSSIBLY understand. But I assure you, you are ALL capable of designing a novel and active opioid agonist.

Of course, the term opioid suggests semi-synthetic - But I hope to show how it's possible to learn the 'rules' of opioids and design your OWN opiate agonist.

I will not hide my goal. To make potent opioids so synthetically simple that EVERYONE can make them.

 

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Just to give a basic insight, here are 12 phenolic opioids that follow the classical phenanthracine class of opiate.

You may think my selection odd but it represents phenolic opioids discovered between then 1940s and the 1980s. As you will discover, the QSAR of phenolic opioids is MUCH more picky than non-phenolic opioids. If people wonder why ring-substituted derivatives of ketobemidone are not known, it's because the WRONG enantiomer is an antagonist.

So, Rule 1.

It is is impossible for a non-phenolic opioid to act as an antagonist. and careful research on viminol isomers shows that some isomers are stimulants... but they are not antagonists..

I might add that I communicated with the discoverer of ketobemidone and he was clear to say that because isomers could not be isolated, many seemingly inactive compounds were never carefully analysed because optical resolution simply wasn't an option. Otto (Eisleb) was QUITE clear that studies of ketobemidone (later shown in picenidol) show that a derivative some x 9 morphine were likely but that production chemistry prevented development (look at picenadol) stopped development.

I merely say what I know. Next time prodine derivatives and WHY only phenolic opioids can be ANTAGONISTS.

 

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BTW I will systematically go through every class of synthetic opioids so you can all see hoe drugs like fentanyl, etonitazine and U-47700 all overlay morphine.

But to be going on, I give you 'tahexanol', a VERY simple tapentadol homologue which has MOR affinity some x12 higher and MOR effacacy that is formlly termed a 'superagonist' i.e. tahexanol is more potent than H,

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I do not say tahexadol is as euphoric as H and it's action on the monoamine systems of the human body generally result in unwanted side-effects such as nausea, vertigo, anxiety, hypervigilance and insomnia. It also has a very long duration of action.

But I believe the key positives of tapentadol is that it does not appear to produce 'addiction' because in the 1990s some people I knew took part in a study concerning the use of tapentadol in heroin detoxification.

Results of the study were POOR.

While MANY opioids alter the monoamines within the CNS of a subject, the most common outcome was people simply becamephysically dependant on tapentadol and a sizable nbumber developed epilepsy (absence seizures) and aphasia (selective mtism).

So while it was able o substitute for classical opioids, it was quickly recognized as producing a significantly increased risk of suicide and related self-harm.

Note that when ketobemidone was developed, Otto Eisleb (also developer of pethidine, bemidone and methdone) wrote in his lab notes that 'the only practical N subsitution was a simple methyl as <other experimental N substitutions> were not chiral and that unlike ring-substitution of prodine and pethidine homolgues, 'it was certain that the orientation of a 3-alkyl would produce equally potent agoniss and antagonists'.

The raecmate was tested and resulted in no significant analgesic activity.

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above is an example of two stereoisomers of ketobemidone. Early studies did not resolve enantiomers BUT the later development proved that one isomer of picenalol is an agonist, the other id an antagonist.

This is why the research on non-phenolic opioid development became so important. While the chirality of ring-substituents of the phenylpiperidine (simplest) class of opioids would alter the activity (one isomer being x0.7 morphine, the other c5.5 morphine) BOTH isomers are agonists. So syntheses in which a significant (but not dangerous( amount of a less potent isomer could br accepted within the final compound.

This is in contrast to 3-alkyl derivatives of ketobemidone where the unwanted isomer could reduce or indeed totally remove all analgesic activity. BUT it's worth noting that without an alkyl side-chain, ketobemidone is still regarded as being some x2.5 times more potent than morphine. In contrast, one of the (S) enantiomers of prodine i(alpha prodine) s estimated as being as potent as morphine while the beta isomer is some x5.5 as potent as morphine.

NOTE FOR STUDENTS - I am attempting to underline that ONLY phenolic (benzene ring bearing a meta -OH moiety) opioids are able to produce antagonist activity. Even within the class of phenolic opioid agonists, the benzylic side-chain can produce everything from antagonist (-CH3 <methyl>) side-chain at benzylic ring, to partial agonist (<-CH2CH3)> and the N-propyl <-CH2CH2CH3)> which is an agonist.

BUT one extra key to the famous 'morphine rule' is: 'non-phenolic opioids cannot produce inverse agonist or antagonist activity'