In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB1 receptor antagonist for the management of obesity
In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB1 receptor antagonist for the management of obesity
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DOI：
10.1016/j.bbrc.2010.03.015
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发表时间：
2010-04-02
影响因子：
3.1
通讯作者：
Scott, Dennis O.
中科院分区：
文献类型：
--
作者：
Hadcock, John R.;Griffith, David A.;Scott, Dennis O.
大麻素 CBI 受体拮抗剂表现出有利于治疗代谢疾病的药理学特性。 CP-945,598 (1-[9-(4-氯苯基1)-8-(2-氯苯基1)-9H-嘌呤-6-基]-4-乙氨基哌啶-4-甲酰胺盐酸盐）是一种最近发现的选择性、高亲和力、竞争性 CB 受体拮抗剂，可在体外和体内抑制基础和大麻素激动剂介导的 CBI 受体信号传导。 CP-945,598 在结合 (K-i = 0.7 nM) 和功能测定 (K-i = 0.2 nM) 中对人类 CBI 受体表现出亚纳摩尔效力。该化合物对人类 CB2 受体具有低亲和力 (K-i = 7600 nM)。在体内，CP-945,598 可逆转四种大麻素激动剂介导的 CNS 驱动的对合成大麻素受体激动剂的反应（运动不足、体温过低、镇痛和僵住）。 CP-945,598 在啮齿动物的两种急性食物摄入模型、快速诱导的再进食和自发的夜间进食模型中表现出剂量和浓度依赖性的厌食活性。 CP-945,598 还强烈刺激大鼠的能量消耗并降低呼吸商，表明代谢转变为增加脂肪氧化。在饮食诱导的肥胖小鼠的 10 天体重减轻研究中，10 mg/kg 的 CP-945,598 促进了 9% 的载体调整体重减轻。浓度/效应关系与离体大脑 CBI 受体占用数据相结合，用于评估行为、食物摄入和能量消耗研究的功效。总之，这些体外、离体和体内数据表明 CP-945,598 是一种新型 CBI 受体竞争性拮抗剂，可以进一步加深我们对内源性大麻素系统的理解。 (C) 2010 Elsevier Inc. 保留所有权利。
Cannabinoid CBI receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chloropheny1)-8-(2-chloropheny1)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB, receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CBI receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CBI receptors in both binding (K-i = 0.7 nM) and functional assays (K-i = 0.2 nM). The compound has low affinity (K-i = 7600 nM) for human CB2 receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10 mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CBI receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CBI receptor competitive antagonist that may further our understanding of the endocannabinoid system. (C) 2010 Elsevier Inc. All rights reserved.