Pharmacological studies of the glutamate blocker and its application to central nervous system depressant

在我们之前的研究中，我们发现一些谷氨酸激动剂如kainic， quisqualic，软骨藻酸和丙烯酸在无脊椎动物和脊椎动物中具有强效的兴奋作用。这些强效谷氨酸受体激动剂的发现建立了谷氨酸受体亚型分类的基础。此外，我们还发现TI-233、tuberostemonine、MLV-208、MLV-5860和MLV-6976等化合物能明显阻断小龙虾神经肌肉连接处的谷氨酸反应。在这些化合物中，一些三亚甲二胺衍生物对大鼠贫血性失脑强直、小鼠药物性震颤和家兔眼球震颤表现出有效的抑制作用，提示谷氨酸阻滞剂可能对中枢运动系统疾病的治疗有用。在本研究中，我们研究了三亚甲二胺，特别是MLV-6976对中枢神经系统的影响。在大鼠贫血性失脑强直中，MLV-6976在剂量范围内呈剂量依赖性抑制强直，其作用小于已建立的中枢作用肌肉松弛剂。MLV-6976对血压有轻微的降低作用，但降低的程度小于托培里森酮。MLV-6976对震颤诱发的震颤有增强作用，而对盐碱诱发的震颤有抑制作用。MLV-6976对小鼠和大鼠自发性运动活动和猫脊髓反射电位没有影响。MLV-6976以开放通道阻断的方式抑制小龙虾神经肌肉连接处的谷氨酸反应。基于这些实验结果，讨论了MLV-6976作为中枢作用治疗药物的可能性。

In our previous studies we found a potent excitatory action of some glutamate agonists such as kainic, quisqualic, domoic and acromelic acids in the invertebrate and vertebrate. The finding of such potent glutamate agonists led to establishment of the base of classification of glutamate receptor subtypes. In addition, we found some compounds such as TI-233, tuberostemonine, MLV-208, MLV-5860 and MLV-6976, which blocked markedly the glutamate response at the crayfish neuromuscular junction. Among these compounds, some trimethylenediamine derivatives showed a potent inhibitory action on rat anaemic decerebrate rigidity, drug-induced tremor in mice, and nystagmus in the rabbit, suggesting that the glutamate blocker might be useful for the treatment of central motor system diseases. In the present study we examined the effect of trimethylenediamine, particularly MLV-6976, on the central nervous system. In the rat anaemic decerebrate rigidity, MLV-6976 depressed the rigidity in a dose-dependent manner in the dose range which was less than that of established centrally acting muscle relaxants. Blood pressure was slightly reduced by MLV-6976, but the degree of the reduction of blood pressure was less than that of tolperisone. MLV-6976 augmented the tremorine-induced tremor, but depressed the harmaline-induced tremor. Spontanoeus motor activities in mice and rats and reflex potentials in the cat spinal cord were not affected by MLV-6976. MLV-6976 depressed the glutamate response at the crayfish neuromuscular junction in an open-channel blocking manner. Based on these experimental results, the possibility of MLV-6976 as a centrally acting therapeutics was discussed.