STRUCTURE-ACTIVITY-RELATIONSHIPS OF TRANS-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE ANTAGONISTS FOR MU-OPIOID AND KAPPA-OPIOID RECEPTORS

A series of racemic N-substituted trans-3,4-dimethyl-4-(3-hydroxypheny l)piperidines were evaluated for opioid agonist and antagonist activit y at mu and kappa receptors. Several highly potent mu and kappa antago nists were discovered; however, no compounds with high selectivity for either the mu or kappa receptor were identified. Importantly, no deri vative was found to have significant opioid agonist activity. Two deri vatives were resolved, and the activities of the enantiomers were inve stigated. Only a limited stereochemical effect on opioid receptor sele ctivities was observed. The structure-activity relationships described establish the existence of an important lipophilic binding site dista l to the nitrogen for both mu and kappa receptors and confirm the pure opioid antagonist pharmacophore nature of the trans-3,4-dimethyl-4-(3 -hydroxyphenyl)piperidine structure.