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Mol Pharmacol. 2015 Aug;88(2):238-44. doi: 10.1124/mol.115.098541. Epub 2015 May 26.

Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists.

Author information

1
Laboratory of Physiologic Studies (M.R.I., R.C., J.L., G.G., G.S., G.K.) and Laboratory of Molecular Physiology (H.P., S.R.I.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Naval Research Laboratory, Washington, D.C. (J.D.); and Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland (Y.-S.L., P.J.S.).
2
Laboratory of Physiologic Studies (M.R.I., R.C., J.L., G.G., G.S., G.K.) and Laboratory of Molecular Physiology (H.P., S.R.I.), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Naval Research Laboratory, Washington, D.C. (J.D.); and Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland (Y.-S.L., P.J.S.) george.kunos@nih.gov.

Abstract

6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain-penetrant compound 14G: [5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2R)-2-hydroxy-cyclohexyl]-3-pyridinecarboxamide] and its peripherally restricted analog 14H: [5-(4-chlorophenyl)-N-[(1R,2R)-2-hydroxycyclohexyl]-6-(2-methoxyethoxy)-3-pyridinecarboxamide], have been recently introduced as selective, high-affinity antagonists of the human cannabinoid-1 receptor (hCB1R). Binding analyses revealed two orders of magnitude lower affinity of these compounds for mouse and rat versus human CB1R, whereas the affinity of rimonabant is comparable for all three CB1Rs. Modeling of ligand binding to CB1R and binding assays with native and mutant (Ile105Met) hCB1Rs indicate that the Ile105 to Met mutation in rodent CB1Rs accounts for the species-dependent affinity of 14G: and 14H: . Our work identifies Ile105 as a new pharmacophore component for developing better hCB1R antagonists and invalidates rodent models for assessing the antiobesity efficacy of 14G: and 14H: .

PMID:
26013543
PMCID:
PMC4518088
DOI:
10.1124/mol.115.098541
[Indexed for MEDLINE]
Free PMC Article

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