Structure-activity relationships of trans-3,4-dimethyl-4-(3- hydroxyphenyl)piperidine antagonists for μ- and κ-opioid receptors

Article abstract of DOI:10.1021/jm00072a001

A series of racemic N-substituted trans-3,4-dimethyl-4-(3- hydroxyphenyl)piperidines were evaluated for opioid agonist and antagonist activity at μ and κ receptors. Several highly potent μ and κ antagonists were discovered; however, no compounds with high selectivity for either the μ or κ receptor were identified. Importantly, no derivative was found to have significant opioid agonist activity. Two derivatives were resolved, and the activities of the enantiomers were investigated. Only a limited stereochemical effect on opioid receptor selectivities was observed. The structure-activity relationships described establish the existence of an important lipophilic binding site distal to the nitrogen for both μ and κ receptors and confirm the pure opioid antagonist pharmacophore nature of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine structure.