Enantiomers of β-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.