TY - JOUR T1 - Structural Basis of Species-dependent Differential Affinity of 6-Alkoxy-5-aryl-3-pyridinecarboxamide Cannabinoid Receptor 1 Antagonists JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.098541 SP - mol.115.098541 AU - Malliga R Iyer AU - Resat Cinar AU - Jie Liu AU - Grzegorz Godlewski AU - Gergo Szanda AU - Henry Puhl AU - Stephen R Ikeda AU - Jeffrey Deschamps AU - Yong-Sok Lee AU - Peter J Steinbach AU - George Kunos Y1 - 2015/05/26 UR - http://molpharm.aspetjournals.org/content/early/2015/05/26/mol.115.098541.abstract N2 - 6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brain penetrant compound 14g and its peripherally restricted analog 14h, have been recently introduced as selective, high affinity antagonists of the human cannabinoid receptor-1 (hCB1R, J. Med. Chem. 56, 9874-96, 2013). 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. ER -