Stereochemical studies on medicinal agents. 25. Absolute configuration and analgetic potency of .beta.-1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine enantiomers

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Abstract
Enantiomers of .beta.-1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine (4) were employed as probes to demonstrate that opioid receptors are capable of distinguishing between the enantiotopic edges (the Ogston effect) of the piperidine ring. These enantiomers, (-)- and (+)-4.cntdot.HCl, were prepared by esterification of the corresponding alcohols, (+)- and (-)-4a. Single crystal X-ray studies of (-)-4a.cntdot.HCl reveal that it possesses the 2R,4S, absolute configuration. Analgetic testing in mice (hot-plate) and receptor binding studies indicate that (-)-(2S,4R)-4.cntdot.HCl is .apprx. 10 times more potent than its enantiomer. The results are consistent with the operation of the Ogston effect in the interaction of achiral 4-phenylpiperidines with opioid receptors. Additionally, it is suggested that the piperidine ring of these and other closely related 4-phenylpiperidines bind within a receptor subsite cleft whose dimensions exclude diequatorial 2,6- and 3,5-dimethyl-substituted ligands.