Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist
Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist
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DOI：
10.1016/j.ejphar.2004.01.015
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发表时间：
2004-03-08
影响因子：
5
通讯作者：
Yao, BB
中科院分区：
文献类型：
--
作者：
Hancock, AA;Bennani, YL;Yao, BB
组胺通过作用于中枢神经系统 (CNS) 受体来影响体内平衡机制，包括食物和水的消耗。突触前组胺 H-3 受体调节组胺和其他神经递质的释放，组胺 H3 受体拮抗剂可增强神经递质的释放。 A-331440 {4'-[3-(3(R)-(二甲氨基)-吡咯烷-1-基)-丙氧基]-联苯-4-甲腈}是一种组胺 H-3 受体拮抗剂，可有效且选择性地与人和大鼠组胺 H-3 受体结合（K-i 小于或等于 25 nM）。在 28 天每日两次口服之前，小鼠以高脂肪饮食（45 kcal% 猪油）稳定。用于测量肥胖相关参数的剂量。 0.5 mg/kg 剂量的 A-331440 对体重没有显着影响，而 5 mg/kg 剂量的 A-331440 与右芬氟拉明 (10 mg/kg) 相比可降低体重。 15 mg/kg 剂量的 A-331440 将体重减轻至与低脂饮食小鼠相当的水平。两个较高剂量可减少体脂，最高剂量还可使胰岛素耐量测试正常化。这些数据表明组胺 H-3 受体拮抗剂 A-331440 具有作为抗肥胖剂的潜力。 (C) 2004 Elsevier B.V. 保留所有权利。
Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H-3 receptors regulate release of histamine and other neurotransmitters, and histamine H3 receptor antagonists enhance neurotransmitter release. A-331440 {4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile} is a histamine H-3 receptor antagonist which binds potently and selectively to both human and rat histamine H-3 receptors (K-i less than or equal to 25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H-3 receptor antagonist, A-331440, has potential as an antiobesity agent. (C) 2004 Elsevier B.V. All rights reserved.