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Insights Into Subtype Selectivity of Opioid Agonists by Ligand-based and sSructure-based methods

3DQSAR

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Insights into subtype selectivity of opioid agonists by ligand-based and structure-based methods
Jianxin Cheng & Guixia Liu & Jing Zhang & Zhejun Xu & Yun Tang
J Mol Model (2011) 17:477–493
DOI 10.1007/s00894-010-0745-1

Sadly my old PC died peacefully in it's sleep a few weeks ago and as such, I no longer possess a digital copy of the title paper. If anyone has it, I would much appreciate it being stashed somewhere on-line.

What I found interesting is that while it identifiers two proximal ring aromatic (RA) functions, two hydrogen-bond acceptors (HBO) functions and a positively ionizable function (PI), it singularly fails to identify the third RA present in the vast majority of high affinity ligands from anilinopiperidines to diphenylpiperidines to phenylcyclohexanols and so forth.

I welcome criticism of the paper and suggestions for compounds to add to the training set.
 
You can access almost every academic paper ever published at Sci-hub.

If this particular paper isn't there, let me know and I can download it through my universities subscription when I get home in 4 to 5 hours from now.
 
Found it on Library Genesis.


It sends you to junk links the first couple of times but eventually it WILL download the .PDF and local is always best - once you have it, you have it.

Cm1 has a stated Ki of 0.05. Now I actually stumbled on the patent concerning this compound some years ago.


Now it's obviously unusual in many ways. 4j obviously APPEARS of most interest but lets be realistic, synthesis is highly complex so it's more that the compound may be of value as a reference.

But I think it's actually more interesting to note Fig 1a (page 485) which provides the relative spatial positions of certain moieties although I'm aware it's incomplete. I'm fairly sure that the lone-pairs of the nitrogen and oxygen linked to adjacent carbons interact.
 

Another interesting paper. While the 'address-message' theory of activity is a rather blunt tool, I'm still a little surprised that nobody appears to have stated that for an opioid to exhibit antagonist activity, it must bear a phenol (or bioisostere) moiety.

I did undertake an extensive search because I had read of a few compounds lacking said moiety behaved as antagonists - but that turned out to be an artifact of presuming that jumping behavior in mice was a reliable metric. The 1S(S,S) enantiomer of viminol was classed as an antagonist for decades until it was discovered not to have MOR affinity but produced jumping mice. Such 'truths' can exist for decades until challanged.

I may mangle the quote and reference but I believe Karl Popper stated that 'experimentation may only prove the falsity of a theorem' or words to that effect.
 
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