Structural basis of species-dependent differential affinity of 6-alkoxy-5-aryl-3-pyridinecarboxamide cannabinoid-1 receptor antagonists

Malliga R. Iyer, Resat Cinar, Jie Liu, Grzegorz Godlewski, Gergö Szanda, Henry Puhl, Stephen R. Ikeda, Jeffrey Deschamps, Yong Sok Lee, Peter J. Steinbach, George Kunos

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Abstract

6-Alkoxy-5-aryl-3-pyridincarboxamides, including the brainpenetrant 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 CB1 Rs 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.

Original languageEnglish
Pages (from-to)238-244
Number of pages7
JournalMolecular pharmacology
Volume88
Issue number2
DOIs
Publication statusPublished - Aug 1 2015

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Iyer, M. R., Cinar, R., Liu, J., Godlewski, G., Szanda, G., Puhl, H., Ikeda, S. R., Deschamps, J., Lee, Y. S., Steinbach, P. J., & Kunos, G. (2015). Structural basis of species-dependent differential affinity of 6-alkoxy-5-aryl-3-pyridinecarboxamide cannabinoid-1 receptor antagonists. Molecular pharmacology, 88(2), 238-244. https://doi.org/10.1124/mol.115.098541