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

Abstract

SUMMARYThe 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 substituents 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 found 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.

Molecular dynamics of fentanyl bound to μ-opioid receptor

“…On the other hand, fentanyl has only one more structural element able to participate in hydrogen bonding (C=O), compared to phenolic and hydroxy -OH and ether -Ogroups of morphine. Fentanyl is also relatively highly flexible, with its seven more or less rotatable bonds (neglecting the CH 3 rotations and possibility for the piperidine ring conformation flips), while morphine is essentially rigid [25][26][27][28].…”

Cysteine-reactive chemical probes based on a modular 4-aminopiperidine scaffold

“…1A). 31 Given the predicted conformation of this scaffold, we designed our probe library to incorporate the electrophile and diversity elements in close proximity as substituents on the exocyclic 4-amino group (Fig. 1B).…”

Fentanyl and Its Analogue N-(1-Phenylpyrazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl]propanamide: 1H- and 13C-NMR Spectroscopy, X-Ray Crystallography, and Theoretical Calculations

“…Despite the importance of fentanyl and the fact that it has been the subject of a large number of structural and conformational studies, [17][18][19][20][21][22][23] the basis of fentanyl binding is still under investigation. 24) According to the Cambridge Crystallographic Database (CSD) 25) the crystal structure of the citrate salt of 1 26) and that of citrate-toluene solvate 27) have been solved.…”