Insights Into Subtype Selectivity of Opioid Agonists by Ligand-Based and Structure-Based Methods (how to design novel opioids)

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'Insights Into Subtype Selectivity of Opioid Agonists by Ligand-Based and Structure-Based Methods' (DOI: 10.1007/s00894-010-0745-1) is the most practical introduction to the use of training-sets in the 3D-QSAR of ligands. In fact, I think that their are at least 2 other moieties for μ affinity that aren't common thus not spotted in this set. As it is, only position & direction of aromatic rings, positively ionizable functions, hydrogen-bond acceptors & hydrophobic parts of molecule & their relative positions are noted.

I believe that:

1)olefinic alkenes seem in allylprodine, 14-cinnamyloxycodeinone & 14-allyloxymetopon and a few others (the -C=C- of those three overlay, by the way)

2)and the second is a second ring aromatic that is some distance from the first. MOST of the potent opioids have 2 aromatics. The first seems to be limited to a benzene, phenol or a closely-matching 6-member aromatic (and a carboxamide is a bioisostere for a phenolic -OH) The second can be MANY 5-membered rings (6 ring aromatics not well studied or not active). YES the aromatic shows up, but isn't matched in this model.

One issue of 'Annual Report in Medicinal Chemistry' showed that along with 2-thiophene (thiofentanyl), a 2-furyl (furylfentanyl), a 2 thioazole (very potent it seems), oxazole, imidiazole and so on. It would appear that the altered potency is LogP. and rate of metabolism.

Now the important thing is that I just happened upon this paper and realized that even a clunky second PC running Linux can install CHARMM which is free. As ChemOffice users will know, finding minimum energy states is slow and imperfect. More than once I have had to start the MIC calculations with the compound 'altered' to avoid local minimum-energy states. Of course, their is some scope for positioning because most examples are only semi-rigid. It might take a whole weekend but if that PC was going to be sat there doing nothing than it's free (or almost) is it not? Now I had some help setting up all of that Linux stuff because I can only program in assembly language so several good friends did a lot for me. I did nothing except spot it's possible utility.

So now people can add their own designs and then seeing how well they do!

I really would love to see us using one of those free, Java programs that convert SMILES<--?IUPAC<--Image if only so we don't keep having to use 3rd party support for images. Of course, sekio is the real expert (thinking of you brother).

I do hope it is of value to people. I have another that compares the various DRI/NRIs (well, classes of stimulant) but as I am sure you know that an aromatic, a benzhydryl and an N: are the only requirements That said, an appropriate training set might tease out another moiety. There are a shed-load of smart people here so I am looking forward to being impressed.

-C-

PS I remain convinced that the p-Br analogue of BDPC (or C-8813) can be replaced with a -CH3 which as a lot of advantages. The more I look, the more I am convinced that 3-Amino-3-phenylpropionamide Derivatives ALSO have a decent (sub-nM) affinity IF they were tertiary amines. Put them next to each other! Now, I am not interested in the phenol-baring analogues as they often act as mixed agonist/antagonists but compound 4a with a dimethyl moiety (rather than a monomethyl) is worth looking into. The synthesis doesn't look THAT complex so I'm hoping SOMEONE is reading this. There are just SO MANY novel opioids.

 

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Of course, like (as) a total idiot, I forgot to point out that be it mono- or di- methyl, the 3-Amino-3-Phenylpropaniomides are chiral. So with the nifty switch to an N-dimethyl moiety, I think the novel non-phenolics WILL work. That would be nice - in a position to know when the DEA doesn't even KNOW if it's active (it will be).

That second aromatic (generally 5 member) isn't even covered by that 3D QSAR paper BUT I think it's a good starting point. It is all very well to come up with any given number of compounds BUT if the precursors are not commercially available and/or can be made simply from a pre-precursor then for forget it.

For those keeping score - U-47700 was made using just 2 commercially available chemicals in a single step. What you do in your 50mL glassware is all very well. What happens in the Chinese 250L glass-lined reactor is not always the same. It has and always will come down to how simple a compound can be made. Of course, the idiots who ordered carfentanil deserve bad things to happen to them. All I can say is that these people are not medicinal chemists and do no care about life. Surely a compound that kills NOBODY is better business, let alone better morally.

Sorry - off soapbox now.

 

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Were the Chinese guys responsible for U-47700 being (apparently, was the reason I didnt mess with it) so overly caustic?

With 2-methyl-AP-237 it's happening again. Asked a German vendor about that, the only one I know of which actually tests their stuff and only sell what they take themselves but got no answer.

Interesting, need to read up about the synth route for U. Remember another AH-7921 relative that was an easy reaction between just two chems but unfortunately I can't find it any more, was on a message board which allowed such discussion and went offline.

Still hope somebody will come up with a selective delta agonist or a balanced mu-delta one and a selective kappa antagonist, maybe even better an inverse agonist if it's true what they say about kappa and addiction/depression.

Was it you who told me that BDPC actually isn't a delta agonist? Interesting because it felt pretty unique, difference to morphine like of that to methadone. More cuddly, silky organic feeling instead of clinical sedation.

 

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Well U-47700 was originally Upjohn's work in the 1970s but no, it was a UK group that originally made it. It was supposed to be in 5mg soluble tablets (so people could swallow. snort or bang up with minimal harm)... but it appeared that the cost was just TOO HIGH. I mean, these are the people who make the original 0.5mg pyrazolam tablets so they KNEW how to make them but the cost was about $12000 a K so any cost over and above (from the £3 million per Kg) was much, much too much. If I sound bitter then it's because I am.

2-methyl-AP-237 MAY be OK but I doubt it. trans-2,6-AP-237 is a lot better BUT I presume that the Chinese aren't resolving isomers so while 50% of the 2-Me-AP237 may only be as potent as AP237 (1/3 M), the 2-me will be x4 more potent because that 2-methyliperazine is rotatable but NOT the dimethyl.

Now U4 was chosen in front of the other option because the other option, though MUCH more euphoric, was only as potent as M so even in bulk, it would only sell for $15000/Kg which apparently wasn't enough. I mentioned it, it's a mu agonist, NMDA angtagonist and DRI which makes it just about the most euphoric opioid known to man (I mean better than Diconal, Dromoran or Ketogan). We had samples made and everyone loved it but intil 2014, no paper helped out with an easy synthesis, now there is one - 2 steps.

But that is how it is. The people making fentanyl are the same people making U4. I would guess that the one I found that Derek P. Reynolds found while working for Glaxo, even with the nice 2-step route would have to be sold at retail prices i.e. $60/g (because $60 K is most certainly a profit).

Honestly, it's been a long strange trip but the people divide into the 'lets give the people an awesome buzz' and the 'what makes the most'? I guess I've never found money the driver. In the late 80s I provided the MDMA for free parties in the UK and it is at once thrilling and scary to see people on your stuff. Proud they like it, always worried someone will be hurt.... but now the people making stuff do not care if people are safe and enjoy - just that they profit and do not get caught.

 

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U-47700 was first made in China for a UK buyer. 1K cost $18K so YOU work out the retail profits.

It seems like the potency doesn't make an difference - the dealers just luck at the price/Kg not working out DOSES per unit so U4 (2 steps from commercially available precursors) only JUST made it.


Of course - being a preprecursor supplier (legal) is the place to be now. I have my own MDMA homologue that doesn't use anything even vaguely watched.... but I do not think anyone here deals with preprecursors (but I could be wrong).