Chaki Shigeyuki, Yoshikawa Ryoko, Hirota Shiho, Shimazaki Toshiharu, Maeda Maoko, Kawashima Naoya, Yoshimizu Takao, Yasuhara Akito, Sakagami Kazunari, Okuyama Shigeru, Nakanishi Shigetada, Nakazato Atsuro
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama 331-9530, Japan.
Neuropharmacology. 2004 Mar;46(4):457-67. doi: 10.1016/j.neuropharm.2003.10.009.
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 high affinity for both mGluR2 (Ki = 2.2 nM) and mGluR3 (Ki = 4.5 nM), which are comparable to LY341495, another group II mGluR antagonist. MGS0039 attenuated both glutamate-induced inhibition of forskolin-evoked cyclic AMP formation in CHO cells expressing mGluR2 (IC50 = 20 nM) or mGluR3 (IC50 = 24 nM) and glutamate-increased [35S]GTPgammaS binding to mGluR2 (pA2 = 8.2), which means that MGS0039 acts as an antagonist. MGS0039 shifted the dose-response curve of glutamate-increased [35S]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 II mGluR, and that group II mGluR antagonists, like MGS0039, have an antidepressant-like potential in experimental animal models.
本研究描述了新型II组代谢型谷氨酸受体（mGluR）拮抗剂（1R,2R,3R,5R,6R）-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（MGS0039）的药理学特征。MGS0039对mGluR2（Ki = 2.2 nM）和mGluR3（Ki = 4.5 nM）均表现出高亲和力，这与另一种II组mGluR拮抗剂LY341495相当。MGS0039减弱了谷氨酸对表达mGluR2（IC50 = 20 nM）或mGluR3（IC50 = 24 nM）的CHO细胞中福斯可林诱发的环磷酸腺苷（cAMP）形成的抑制作用，以及谷氨酸增加的[35S]GTPγS与mGluR2的结合（pA2 = 8.2），这意味着MGS0039作为拮抗剂发挥作用。MGS0039使谷氨酸增加的[35S]GTPγS结合的剂量反应曲线向右移动，而不改变最大反应，从而表明其具有竞争性拮抗作用。MGS0039对我们研究的其他mGluR以及其他受体和转运体均无显著影响。MGS0039（0.3 - 3 mg/kg，腹腔注射）以及LY341495（0.1 - 3 mg/kg，腹腔注射）在大鼠强迫游泳试验和小鼠悬尾试验中具有剂量依赖性的抗抑郁样作用。相比之下，MGS0039（0.3 - mg/kg，腹腔注射）在大鼠社交互动试验和大鼠高架十字迷宫试验中没有明显作用。这些结果表明，MGS0039是一种强效且选择性II组mGluR拮抗剂，并且像MGS0039这样的II组mGluR拮抗剂在实验动物模型中具有抗抑郁样潜力。
