Back to Search
Start Over
Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2-methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2013 Jun 13; Vol. 56 (11), pp. 4551-67. Date of Electronic Publication: 2013 May 16. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Benzamides chemistry
Benzamides pharmacology
CHO Cells
Cricetinae
Cricetulus
Guanosine 5'-O-(3-Thiotriphosphate) metabolism
Humans
Molecular Docking Simulation
Piperazines chemistry
Piperazines pharmacology
Radioligand Assay
Receptors, Opioid, delta agonists
Receptors, Opioid, delta antagonists & inhibitors
Receptors, Opioid, kappa agonists
Receptors, Opioid, mu agonists
Receptors, Opioid, mu antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Benzamides chemical synthesis
Piperazines chemical synthesis
Receptors, Opioid, kappa antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 56
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23651437
- Full Text :
- https://doi.org/10.1021/jm400275h