Synthesis and In Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa Opioid Receptor Antagonist (3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic)
| Autor: | Zhou Zou, Tingwei Bill Cai, Hernán A. Navarro, F. Ivy Carroll, James B. Thomas, Larry Brieaddy |
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| Rok vydání: | 2008 |
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| Zdroj: | Journal of Medicinal Chemistry. 51:1849-1860 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm701344b |
| Popis: | In previous structure–activity relationship (SAR) studies, we identified (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective κ opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [35S]GTPγS binding assay. The results from the studies better define the pharmacophore for this class of κ opioid receptor antagonist and has identified new potent and selective κ antagonist. (3R)-7-Hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3) with a Ke value of 0.03 nM at the κ receptor and 100- and 793-fold selectivity relative to the μ and δ receptors was the most potent and selective κ opi... |
| Databáze: | OpenAIRE |
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