title: Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders.
abstract: 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 (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu 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 mu opioid receptor involvement in GI motility disorders.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.
authors.forename: D M
authors.initials: DM
authors.lastname: Zimmerman
authors.forename: J S
authors.initials: JS
authors.lastname: Gidda
authors.forename: B E
authors.initials: BE
authors.lastname: Cantrell
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: B G
authors.initials: BG
authors.lastname: Johnson
authors.forename: J D
authors.initials: JD
authors.lastname: Leander
mesh_terms: D000818:Animals; D003967:Diarrhea / Q000139:chemically induced; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007410:Intestinal Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D017450:Receptors, Opioid, mu