Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia

[4DQSAR]

https://www.sciencedirect.com/science/article/abs/pii/S2451945624002721#:~:text=Through%20high-throughput%20screening%20and%20structure-activity%20relationship%20studies%2C%20we,morphinan%20antagonists%2C%20which%20induce%20G%20protein-dependent%20MOR%20activation.

Now let's be clear - this appears to be early in vitro modelling. But it WOULD be ironic it it actually works. If consumed alone, the compound isn't psychoactive (as far as I know) but if it makes morphinan class antagonists into agonists, it is still unknown if the combination will provide the same psychoactive effects as a traditional agonist. So a lot of unknowns hence my not posting it in the hope that the researcher would provide more answers. But I SUSPECT they are equally concerned of possible abuse.

So don't get too excited. We always knew that it was the orientation of the basic nitrogen's lone-pair that mediated a morphinans agonist or antagonist activity. So it's entirely possible (from the limited infomation) to suggest that what BPRMU191 is actually doing is altering that lone-pair in some manner.

But who knows if it will ever be used. That para fluoro may be a requirement for binding or equally may be present to slow down metabolism or indeed BOTH.

BTW I checked and in what I suspect to be the first step in 'evergreening' their potential medicine, the candidates is a raecemate of both enantiomers. I DID ask and no, they won't say. But that ortho methyl is quite clearly there to fix the rotation angle relative to both the para fluoro phenyl ring AND the 1,3-thiazolidin-4-one ring. I'm sure nobody is surprised that a trans rather than cis relationship exists between the two aromatics.

 

[Smyth2]

I don't know this for certain, but wouldn't the ortho-methyl group serve the purpose of shielding the amide from metabolism?

 

[4DQSAR]

I don't know this for certain, but wouldn't the ortho-methyl group serve the purpose of shielding the amide from metabolism?

Look at the minimum-energy conformation without that ortho methyl. It's very common for ortho methyls to be used to fix relative orientations. Cm1 of that paper concerning training sets has two ortho methyls and if you do a bit more research, you find that a single ortho substitution offered two minimum-energy conformations so demonstrated less activity. Just an example. But in this case, I suggest you only need one because one conformation is in a much lower energy state than the other.

So far it's only in vitro models so metabolism won't have been considered in depth which is why I suggested that the para fluoro WILL prevent hydroxylation but may well be an optimal fit for that lipophilic pocket opioids with the N-2-phenylethyl moiety. p-F OHMeFentanyl being an example of a cheeky p-F improving affinity. Because it's possible or even likely that the candidate is filling the very same lipophilic pocket. Which in turn would alter the orientation of the N-substitution of the antagonist thus making it an agonist.

I'm not asserting that the ortho methyl WON'T somehow protect that 1,3-thiazolidin-4-one ring, but nobody is going to try too hard because who knows what in vitro models will show? It's entirely possible that it isn't useful for one reason or another but you can assume that if this is BPRMU191, BPRMU1-BPRMU190 are also known to the researchers and if this one doesn't work, they can use the others to probe the human receptors. In fact, I would assume that at some stage 18F was used to allow PET. That or it's a placeholder so they CAN perform 18F PET in future. So there are many possibilies. Could be all, could be none - could be something else entirely. But HTS means hit-to-lead is much faster than it was in the 70s and 80s.

Early days. Which is why I waited for six months in the hope of more data but none was forthcoming. The fact they DON'T resolve the enantiomers and refuse to say which is the (more) active is classic research. If the raecemate works, you can patent that and have 7 years (or so) where you own the patent. BUT then you can simply apply for a new patent that specifies the (more) active enantiomer. Since far, far less work is involved in getting a licence for an enantiopure derivative of a raecamic compound, you likely get another 17 years of patent protection. That is what I mean by 'evergreening' although they do lots of things. One medicine had certain hydrogen atoms substituted for deutirium atoms and the result was a slightly better medicine... and two decades of patent protection.