title: Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.
abstract: The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.
authors.affiliation: Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, USA. blebourdonnec@adolor.com
authors.forename: Bertrand
authors.initials: B
authors.lastname: Le Bourdonnec
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Goodman
authors.forename: Mathieu
authors.initials: M
authors.lastname: Michaut
authors.forename: Hai-Fen
authors.initials: HF
authors.lastname: Ye
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Graczyk
authors.forename: Serge
authors.initials: S
authors.lastname: Belanger
authors.forename: Torsten
authors.initials: T
authors.lastname: Herbertz
authors.forename: Glenn P A
authors.initials: GP
authors.lastname: Yap
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010880:Piperidines; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)