Absolute configurations and conformations of the opioid agonist and antagonist enantiomers of picenadol.

Abstract

The absolute configurations of the enantiomers of the opioid picenadol [cis-1,3-dimethyl-4-propyl-4-(3-hydroxyphenyl)piperidine; cis-3-methyl, 4-propyl] have been determined by an X-ray crystallographic study of the chloride salt of the (+)-enantiomer. The agonist (+)-enantiomer and the antagonist (-)-enantiomer were found to have the 3R,4R and 3S,4S absolute configurations, respectively. The conformational properties of the enantiomers were also examined with MM2-87 calculations. There was good agreement between the computed global minimum and the crystallographic structure with the phenyl ring approximately bisecting the piperidine ring by both methods. This orientation of the phenyl ring differs from that of related opioids such as the phenylmorphans, prodines, meperidine, and ketobemidone in which the phenyl ring tends to eclipse one edge of the piperidine ring. Because the phenyl ring bisects the piperidine ring in picenadol, there is little difference in the three-dimensional orientations of the phenyl rings of the two enantiomers when one superimposes the piperidine rings. The agonist (+)-enantiomer is ambiguous with respect to an opioid ligand model, which suggests that agonist activity requires a specific range of dihedral angles for the phenyl ring. While the global minimum of the agonist is not consistent with the model, a second conformer that is only 1.2 kcal/mol above the global minimum is consistent. An alternative explanation is that agonist or antagonist activity is solely due to the presence of the 3-methyl group on the different edges of the piperidine ring.(ABSTRACT TRUNCATED AT 250 WORDS)