Conformational study of fentanyl and its analogs.1. Conformational space of the N‐phenethyl substituent

Abstract

SUMMARY The computational method, based on molecular mechanics, with Monte Carlo type searching in dihedral angle space, was applied to the study of seven physiologically highly active fentanyl analogs, with different subs tituents in a phenethyl side chain. The low energy regions of the conformational space of these molecules have been compared in an effort to establish the receptor-recognized conformation of a phenethyl side chain, and to explain the mechanisms by which a hydroxyl substituent increases potency of the fentanyl analogs. It has been f ound that the extended conformation of a phenethyl side chain is the only one available to all the active analogs of fentanyl. Activities of the compounds with alkyl substituents in the phenethyl side chain correlate with their hydrophobicities. A hydroxyl substituent affects potency by reducing the flexibility of the phenethyl side chain, by reducing the energy difference between the global minimum and the receptor-recognized conformation and by specific interactions with the receptor.