title: Effect of the 3- and 4-methyl groups on the opioid receptor properties of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines.
abstract: N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a,b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a,b, we synthesized analogues of 2a,b that lacked the 4-methyl (5a,b), 3-methyl (6a,b), and both the 3- and 4-methyl group (7a,b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were nonselective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts, and (3) compounds 2a,b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogues 5a,b, 6a,b, and 7a,b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a,b) gives (4a,b), which are opioid antagonists.
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Kormos
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Cueva
authors.forename: Moses G
authors.initials: MG
authors.lastname: Gichinga
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Brieaddy
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: D009292:Narcotic Antagonists; D010880:Piperidines