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.
Footnotes
- Received February 20, 2015.
- Accepted May 26, 2015.
M.R.I. and R.C. contributed equally to this work.
This study was supported by the National Institutes of Health Intramural Research Programs of the National Institute of Alcohol Abuse and Alcoholism and of the Center for Molecular Modeling, Center for Information Technology. The X-ray crystallographic work was supported by the National Institute on Drug Abuse through Interagency Agreement [Grant Y1-DA1101] with the Naval Research Laboratory.
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