Discovery of a Potent, Peripherally Selective trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonist for the Treatment of Gastrointestinal Motility Disorders

Article abstract of DOI:10.1021/jm00041a003

Structure-activity relationship studies were pursued within N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration.Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736).Compound 3 has high affinity for opioid receptors (K_i = 0.77, 40, and 4.4 nM for μ, κ, and δ receptors, respectively).It is a potent μ receptor antagonist following parenteral and oral administration and distributes selectively (>200-fold selectivity) to peripheral receptors.Thus, 3 has properties suitable for the clinical investigation of μ opioid receptor involvement in GI motility disorders.