6-烷氧基-5-芳基-3-吡啶甲酰胺类大麻素-1受体拮抗剂物种依赖性差异亲和力的结构基础
Structural Basis of Species-Dependent Differential Affinity of 6-Alkoxy-5-Aryl-3-Pyridinecarboxamide Cannabinoid-1 Receptor Antagonists.
作者信息
Iyer Malliga R, Cinar Resat, Liu Jie, Godlewski Grzegorz, Szanda Gergö, Puhl Henry, Ikeda Stephen R, Deschamps Jeffrey, Lee Yong-Sok, Steinbach Peter J, Kunos George
机构信息
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.).
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.)
出版信息
Mol Pharmacol. 2015 Aug;88(2):238-44. doi: 10.1124/mol.115.098541. Epub 2015 May 26.
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: .
6-烷氧基-5-芳基-3-吡啶甲酰胺，包括可穿透血脑屏障的化合物14G：[5-(4-氯苯基)-6-(环丙基甲氧基)-N-[(1R,2R)-2-羟基环己基]-3-吡啶甲酰胺]及其外周受限类似物14H：[5-(4-氯苯基)-N-[(1R,2R)-2-羟基环己基]-6-(2-甲氧基乙氧基)-3-吡啶甲酰胺]，最近已作为人大麻素-1受体（hCB1R）的选择性高亲和力拮抗剂被引入。结合分析表明，这些化合物对小鼠和大鼠CB1R的亲和力比对人CB1R低两个数量级，而利莫那班对所有三种CB1R的亲和力相当。配体与CB1R结合的模型以及与天然和突变型（Ile105Met）hCB1R的结合试验表明，啮齿动物CB1R中Ile105到Met的突变导致了14G和14H的物种依赖性亲和力。我们的工作确定Ile105是开发更好的hCB1R拮抗剂的新药效团成分，并使评估14G和14H抗肥胖疗效的啮齿动物模型无效。
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