• Article

Ohmefentanyl and its stereoisomers: Chemistry and pharmacology

Ohmefentanyl, or beta-hydroxy-3-methylfentanyl, is an unique member of the 4-anilidopiperidine class of opiates. This review summarizes both the initial studies on mixtures of ohmefentanyl stereoisomers and some more recent studies on the eight individual stereoisomers, in particular those in which the 3-methyl and 4-propionanilide substituents on the piperidine ring have a cis relationship to each other. Analog studies, also on stereoisomer mixtures, have revealed that structural changes in the beta-hydroxy-beta-phenethyl portion of the molecule have considerable impact on the biological activity in the cis series while changes in the 4-propionanilide portion have smaller effects. The analog data are consistent with the idea that the cis-3-methyl group, the beta-hydroxyl group and the beta-phenethyl group play key roles in cis-ohmefentanyl's unique activity. Biological studies on the four cis-stereoisomers [(beta S,3R,4S)-4a, (beta R,3R,4S)-4b, (beta R,3S,4R)-4c, (beta S,3S,4R)-4d] have shown that they differ considerably in their in vitro and in vivo biological properties. Since these stereoisomers differ from each other in their absolute stereochemistries, which focuses the analysis on asymmetric structural factors and avoids confounding changes in physiochemical characteristics, they constitute a unique set of molecular probes for investigation of mu receptor mediated phenomena. We summarize in this review data showing that these four cis-stereoisomers are characterized by different parameter profiles for ligand-receptor interaction: binding affinity (Ki value), potency (ED50 for receptor activation), efficacy (maximal response) and intrinsic efficacy (relationship between receptor occupation and response). We speculate that the different profiles result from binding to different domains of the mu opioid receptor. Moreover, we expect that continued studies with these stereoisomers, as well as the corresponding stereoisomers of selected cis-ohmefentanyl analogs, will help to elucidate the molecular basis of these parameters and to develop more refined pharmacophores for the opioid mu receptor. This review traces the evolution of ohmefentanyl, or beta-hydroxy-3-methylfentanyl, from the initial papers on the identification of an unexpectedly potent congener of cis-3-methylfentanyl to some of the more recent work involving the four pure cis-stereoisomers and ligands derived from cis-A-ohmefentanyl. While an effort is made to place the discovery of ohmefentanyl into the context of earlier work on 4-anilidopiperidines and then to follow a chronological sequence of events, the review has been organized so that related work from different groups is covered. in the same section. Some of the initial biological data on ohmefentanyl from the Shanghai Institute of Materia Medica was summarized previously in a short review [1].


Brine, G., Carroll, F., RichardsonLeibert, TM., Xu, H., & Rothman, RB. (1997). Ohmefentanyl and its stereoisomers: Chemistry and pharmacology. Current Medicinal Chemistry, 4(4), 247-270.