title: Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists.
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: .
authors.affiliation: 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.).
authors.forename: Malliga R
authors.initials: MR
authors.lastname: Iyer
authors.affiliation: 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.).
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: 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.).
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: 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.).
authors.forename: Gergö
authors.initials: G
authors.lastname: Szanda
authors.affiliation: 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.).
authors.forename: Henry
authors.initials: H
authors.lastname: Puhl
authors.affiliation: 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.).
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Ikeda
authors.affiliation: 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.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Deschamps
authors.affiliation: 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.).
authors.forename: Yong-Sok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: 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.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Steinbach
authors.affiliation: 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.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D063387:Cannabinoid Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007532:Isoleucine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D000077285:Rimonabant; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: C000601050:5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-(2-hydroxycyclohexyl)-3-pyridinecarboxamide; C000601051:5-(4-chlorophenyl)-N-(2-hydroxycyclohexyl)-6-(2-methoxyethoxy)-3-pyridinecarboxamide; C571130:CNR1 protein, human; C578453:CNR1 protein, mouse; D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D007532:Isoleucine; D009536:Niacinamide; D000077285:Rimonabant