DISCOVERY OF A POTENT, PERIPHERALLY SELECTIVE TRANS-3,4-DIMETHYL-4-(3-HYDROXYPHENYL)PIPERIDINE OPIOID ANTAGONIST FOR THE TREATMENT OF GASTROINTESTINAL MOTILITY DISORDERS

Structure-activity relationship studies were pursued within -trans-3,4 -dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a pe ripherally selective opioid antagonist with high activity following sy stemic administration. Altering the size and the polarity of the N-sub stituent led to the discovery of 3 (LY246736). Compound 3 has high aff inity for opioid receptors (K-i = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagon ist following parenteral and oral administration and distributes selec tively (>200-fold selectivity) to peripheral receptors. Thus, 3 has pr operties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.