title: The discovery and development of the N-substituted trans-3,4-dimethyl-4-(3'-hydroxyphenyl)piperidine class of pure opioid receptor antagonists.
abstract: N-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines are a class of pure opioid receptor antagonists with a novel pharmacophore. This opioid receptor antagonist pharmacophore was used as a lead structure to design and develop several interesting and useful opioid receptor antagonists. In this review we describe: 1) early SAR studies that led to the discovery of LY255582 and analogues that are nonselective opioid receptor antagonists developed for the treatment of obesity; 2) the discovery and commercialization of LY246736 (alvimopan; ENTEREG®), a peripherally selective opioid receptor antagonist that accelerates the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis; and 3) the discovery and development of the potent and selective κ opioid receptor antagonist JDTic and analogues as potential pharmacotherapies for treating depression, anxiety, and substance abuse (nicotine, alcohol, and cocaine). In addition, the use of JDTic for obtaining the X-ray structure of the human κ opioid receptor is discussed.
authors: Research Triangle Institute, Center for Organic and Medicinal Chemistry, 3040 Cornwallis Road, Research Triangle Park, NC 27709 (USA). fic@rti.org.
authors: F Ivy
authors: FI
authors: Carroll
authors: Roland E
authors: RE
authors: Dolle
mesh_terms: D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C419502:alvimopan
keywords: JDTic; alvimopan; drug design; medicinal chemistry; opioid antagonists