title: Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists.
abstract: There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [(35)S]GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [(35)S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [(35)S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.
authors: Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA.
authors: Chad M
authors: CM
authors: Kormos
authors: Chunyang
authors: C
authors: Jin
authors: Juan Pablo
authors: JP
authors: Cueva
authors: Scott P
authors: SP
authors: Runyon
authors: James B
authors: JB
authors: Thomas
authors: Lawrence E
authors: LE
authors: Brieaddy
authors: S Wayne
authors: SW
authors: Mascarella
authors: Hernán A
authors: HA
authors: Navarro
authors: Brian P
authors: BP
authors: Gilmour
authors: F Ivy
authors: FI
authors: Carroll
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; C582921:N-(1-((4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl)methyl)-2-methylpropyl)-4-phenoxybenzamide; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
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