title: Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4-(3-Hydroxyphenyl)piperidine Opioid Receptor Antagonists.
abstract: In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [35S]GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties.
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Kormos
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Moses G
authors.initials: MG
authors.lastname: Gichinga
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.affiliation: Naval Research Laboratory, Code 6910, 455 Overlook Avenue, Washington, D.C. 20375, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Imler
authors.affiliation: Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D015195:Drug Design; D015394:Molecular Structure; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D001643:Bridged Bicyclo Compounds; D009292:Narcotic Antagonists; D010880:Piperidines