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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 ? 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]GTP?S binding assay showed that neither compound showed the high potency and ? 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]GTP?S binding stimulated by the selective ? 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 ? opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [(35)S]GTP?S binding assay showed that several of the analogues were potent and selective ? opioid receptor antagonists.

SUBMITTER: Kormos CM 

PROVIDER: S-EPMC3701944 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists.

Kormos Chad M CM   Jin Chunyang C   Cueva Juan Pablo JP   Runyon Scott P SP   Thomas James B JB   Brieaddy Lawrence E LE   Mascarella S Wayne SW   Navarro Hernán A HA   Gilmour Brian P BP   Carroll F Ivy FI  

Journal of medicinal chemistry 20130516 11

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 compound  ...[more]

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