MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity
MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity
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DOI：
10.1016/j.neuropharm.2003.10.009
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发表时间：
2004-03-01
影响因子：
4.7
通讯作者：
Nakazato, A
中科院分区：
文献类型：
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作者：
Chaki, S;Yoshikawa, R;Nakazato, A
本研究描述了新型II组mGluR拮抗剂（1 R，2 R，3R，5 R，6 R）-2-氨基-3-（3，4-二氯苄氧基）-6-氟双环[3.1.0]己烷-2，6-二羧酸（MGS 0039）的药理学特征。MGS 0039对mGluR 2（Ki = 2.2 nM）和mGluR 3（Ki = 4.5 nM）均显示出高亲和力，其与另一种第11组mGluR拮抗剂LY 341495相当。在表达mGluR 2（IC（50）= 20 nM）或mGluR 3（IC（50）=24 nM）的CHO细胞中，MGS 0039减弱了谷氨酸诱导的对毛喉素诱发的环AMP形成的抑制，并减弱了谷氨酸增加的[（35）S] GTP γ S与mGluR 2的结合（pA 2 = 8.2），这意味着MGS 0039作为拮抗剂发挥作用。MGS 0039使谷氨酸增加的[（35）S] GTP γ S结合酶的剂量-反应曲线移动，而不改变最大反应，从而表明竞争性拮抗作用。MGS 0039对其他mGluRs以及我们研究的其他受体和转运蛋白无显著影响。MGS0039（0.3-3 mg/kg，i.p.）以及LY 341495（0.1-3 mg/kg，i. p.）在大鼠强迫游泳试验和小鼠悬尾试验中具有剂量依赖性抗抑郁样作用。相比之下，MGS 0039（0.3-3 mg/kg，i. p.）在大鼠社会互动试验和大鼠高架十字迷宫中无明显作用。这些结果表明，MGS 0039是第11组mGluR的有效和选择性拮抗剂，第11组mGluR拮抗剂，如MGS 0039，。在实验动物模型中具有抗抑郁药样潜力。(C)2003 Elsevier Ltd.保留所有权利。
The present Study describes the pharmacological profile of (1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a novel group II mGluR antagonist. MGS0039 showed hi It affinity for both mGluR2 (Ki = 2.2 nM) and mGluR3 (Ki = 4.5 nM), which are comparable to LY341495, another group 11 mGluR antagonist. MGS0039 attenuated both glutamate-induced inhibition of forskolin-evoked cyclic AMP formation in CHO cells expressing mGluR2 (IC(50) = 20 nM) or mGluR3 (IC(50)=24 nM) and glutamate-increased [(35)S]GTPgammaS binding to mGluR2 (pA2 = 8.2), which means that MGS0039 acts as an antagonist. MGS0039 shifted the dose-response curve of glutamate-increased [(35)S]GTPgammaS binding rightward without altering the maximal response, and thereby indicating competitive antagonism. MGS0039 showed no significant effects on other mGluRs as well as the other receptors and transporters we studied. MGS0039 (0.3-3 mg/kg, i.p.) as well as LY341495 (0.1-3 mg/kg, i.p.) had dose-dependent antidepressant-like effects in the rat forced swim test and in the mouse tail suspension test. In contrast, MGS0039 (0.3-3 mg/kg, i.p.) had no apparent effect in the rat social interaction test and in the rat elevated plus-maze. These results indicate that MGS0039 is a potent and selective antagonist of group 11 mGluR, and that group 11 mGluR antagonists, like MGS0039,. have an antidepressant-like potential in experimental animal models. (C) 2003 Elsevier Ltd. All rights reserved.