Kato Taro, Takata Makoto, Kitaichi Maiko, Kassai Momoe, Inoue Mitsuhiro, Ishikawa Chihiro, Hirose Wataru, Yoshida Kozo, Shimizu Isao
Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Research Planning & Intelligence, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Eur J Pharmacol. 2015 Jun 15;757:11-20. doi: 10.1016/j.ejphar.2015.03.024. Epub 2015 Mar 28.
Modulation of monoaminergic systems has been the main stream of treatment for patients with mood disorders. However, recent evidence suggests that the glutamatergic system plays an important role in the pathophysiology of these disorders. This study pharmacologically characterized a structurally novel metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulator, DSR-98776, and evaluated its effect on rodent models of depression and mania. First, DSR-98776 in vitro profile was assessed using intracellular calcium and radioligand binding assays. This compound showed dose-dependent inhibitory activity for mGlu5 receptors by binding to the same allosteric site as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a known mGlu5 inhibitor. The in vivo therapeutic benefits of DSR-98776 were evaluated in common rodent models of depression and mania. In the rat forced swimming test, DSR-98776 (1-3mg/kg) significantly reduced rats immobility time after treatment for 7 consecutive days, while paroxetine (3 and 10mg/kg) required administration for 2 consecutive weeks to reduce rats immobility time. In the mouse forced swimming test, acute administration of DSR-98776 (10-30 mg/kg) significantly reduced immobility time. This effect was not influenced by 4-chloro-DL-phenylalanine methyl ester hydrochloride-induced 5-HT depletion. Finally, DSR-98776 (30 mg/kg) significantly decreased methamphetamine/chlordiazepoxide-induced hyperactivity in mice, which reflects this compound antimanic-like effect. These results indicate that DSR-98776 acts as an orally potent antidepressant and antimanic in rodent models and can be a promising therapeutic option for the treatment of a broad range of mood disorders with depressive and manic states.
单胺能系统的调节一直是情绪障碍患者治疗的主流方法。然而，最近的证据表明，谷氨酸能系统在这些疾病的病理生理学中起着重要作用。本研究从药理学角度对一种结构新颖的代谢型谷氨酸5（mGlu5）受体负变构调节剂DSR-98776进行了表征，并评估了其对啮齿动物抑郁和躁狂模型的影响。首先，使用细胞内钙和放射性配体结合试验评估了DSR-98776的体外特性。该化合物通过与已知的mGlu5抑制剂2-甲基-6-（苯乙炔基）-吡啶（MPEP）结合到相同的变构位点，对mGlu5受体表现出剂量依赖性抑制活性。在常见的啮齿动物抑郁和躁狂模型中评估了DSR-98776的体内治疗效果。在大鼠强迫游泳试验中，连续7天给予DSR-98776（1-3mg/kg）可显著缩短大鼠的不动时间，而帕罗西汀（3和10mg/kg）则需要连续给药2周才能缩短大鼠的不动时间。在小鼠强迫游泳试验中，急性给予DSR-98776（10-30mg/kg）可显著缩短不动时间。这种作用不受4-氯-DL-苯丙氨酸甲酯盐酸盐诱导的5-羟色胺耗竭的影响。最后，DSR-98776（30mg/kg）可显著降低甲基苯丙胺/氯氮卓诱导的小鼠多动，这反映了该化合物的抗躁狂样作用。这些结果表明，DSR-98776在啮齿动物模型中具有口服有效的抗抑郁和抗躁狂作用，可能是治疗广泛的抑郁和躁狂状态情绪障碍的有前途的治疗选择。
