Stereochemical studies on medicinal agents. 25. Absolute configuration and analgetic potency of beta-1,2-dimethyl-2-phenyl-4-(propionyloxy)piperidine enantiomers.
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.HCl, were prepared by esterification of the corresponding alcohols, (+)- and (-)-4a. Single crystal X-ray studies of (-)-4a.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.HCl is approximately ten 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.
D000700:Analgesics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D010880:Piperidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D010880:Piperidines; D011957:Receptors, Opioid; C034842:1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine