Conformational equilibra of hydrochloride salts of pethidine, ketobemidone, and related central analgesics of the 4-arylpiperidine class

Abstract

The n.m.r. (¹H, ¹³C) spectra of hydrochloride salts of pethidine, ketobemidone, 4-m-hydroxyphenyl-1,4-dimethylpiperidine, and the reversed ester of pethidine and its analogues are reported. Analysis of the data shows that, apart from the reversed esters, both N-protonated epimers are significantly populated when the salts are dissolved in D₂O. The equatorial 4-aryl chair conformer is the major epimer of pethidine and ketobemidone, but the minor form in the case of the 1,4-dimethyl derivative. Little evidence for axial 4-aryl chair epimers has been found for solutes of the reversed esters of pethidine. The results corroborate previous computational studies, and are discussed in terms of differing binding modes of the two classes of 4-arylpiperidine ligand at opioid receptors.