Novel opioid Scaffold

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ChemInform vol. 31 iss. 28 pp.no—no ChemInform Abstract: Design, Synthesis, and Biological Evaluation of 3-Amino-3-phenylpropionamide Derivatives as Novel μ Opioid Receptor Ligands. DOI: 10.1002/chin.200028087 a a	Martin P. Allen; James F. Blake; Dianne K. Bryce; Mary E. Haggan; Spiros Liras; Stafford McLean; Barb E. Segelstein		2010 June 07
	Bioorganic & Medicinal Chemistry Letters vol. 10 iss. 6 pp.523—526 Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel μ opioid receptor ligands DOI: 10.1016/s0960-894x(00)00034-2 a a	Martin P. Allen; James F. Blake; Dianne K. Bryce; Mary E. Haggan; Spiros Liras; Stafford McLean; Barb E. Segelstein		2000 March		English

 

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From the first reference, note that the ligand with the HIGHEST affinity is the N-cyclopropylmethyl-N-methyl derivative.

But the latter doesn't detail ANY examples with a tertiary amine. Neither does it examine the enantiomers. Is it possible that both are equally active but I would argue unlikely.

Like ciramidol, dimetadine, trans-BDPC, lefetamine, doxicopamine and a few others, this class possesses a benzylamine moiety. All of those are most active with an N,N-dimethyl moiety and the chiral examples all demonstrate the (R) enantiomer to be the active, it seems highly likely that:

(R)-2,2-dimethyl-3-(dimethylamino)-3-phenyl-N-(2-phenylethyl)propanamide (as yet not recorded as having been synthesized) is likely to be the most potent AGONIST.

It's worth noting that Table 9-12 on page 417 of 'Opiates' by Lenz et all demonstrates that N-desmethylmethadone (ED50 53.9( is an order of magnitude lower than methadone (ED50 5.2) a ratio common to the metabolites of many opioids containing an N,N-dimethyl moiety.

Sadly the relative affinity data for N,N-dimethyl containing opioids and their N-desmethyl metabolites isn't available due to the time when they were discovered, it isn't possible to confirm if demethylation reduces affinity OR reduces agonist activity OR both of those variables.

While the derivatives bearing a meta -OH on the B-ring demonstrate higher affinity, it seems that like the m-OH homologues of BDPC, they will demonstrate antagonist activity. It's worth noting that homologues lacking said m-OH are significantly simpler to produce.

Given that this compound has never been synthesized (or at least their is no record of such), it would not be controlled by an law. It's structurally unrelated to any other opioid.

 

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4,4-Dimethyl-5-(dimethylamino)-5-phenylvalerophenone

4,4-Dimethyl-5-(dimethylamino)-5-phenylvalerophenone | C21H27NO | CID 200902 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

https://libgen.li/ads.php?md5=800ea9179d6f839e12d1c65d82944fc2&downloadname=10.1021/jm00320a007

It would appear that I've identified a useful motif for simplifying the search for novel opioids.

Note that due to the synthesis, it wasn't possible to ring-substitute just the A aromatic.

Don't forget that when Ciba developed etonitazene it was because 1-(β-diethylaminoethyl)-2-benzylbenzimidazole was noted to possess 10% the analgesic activity of morphine. That was enough to spur rational design which lead to a compound some x1500 morphine in potency. Note that example 10 of the above is also around 10% the potency of morphine,

BTW as far as I can tell, resolution of the enantiomers was never carried out but I think we can tentatively suggest that the (R) isomer will prove to be the active.