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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

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 and George Kunos
Molecular Pharmacology August 2015, 88 (2) 238-244; DOI: https://doi.org/10.1124/mol.115.098541
Malliga R. Iyer
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.)
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Resat Cinar
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.)
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Jie Liu
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.)
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Grzegorz Godlewski
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.)
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Gergö Szanda
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.)
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Henry Puhl
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.)
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Stephen R. Ikeda
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.)
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Jeffrey Deschamps
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.)
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Yong-Sok Lee
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.)
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Peter J. Steinbach
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.)
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George Kunos
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.)
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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.

  • dx.doi.org/10.1124/mol.115.098541.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
Vol. 88, Issue 2
1 Aug 2015
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Rapid CommunicationAccelerated Communication

Species-Specific Affinity of CB1 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 and George Kunos
Molecular Pharmacology August 1, 2015, 88 (2) 238-244; DOI: https://doi.org/10.1124/mol.115.098541

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Rapid CommunicationAccelerated Communication

Species-Specific Affinity of CB1 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 and George Kunos
Molecular Pharmacology August 1, 2015, 88 (2) 238-244; DOI: https://doi.org/10.1124/mol.115.098541
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