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

在我们以前的研究中，我们发现了一些谷氨酸激动剂如红藻氨酸、使君子酸、软骨藻酸和丙烯酸在无脊椎动物和脊椎动物中的强兴奋作用。这种有效的谷氨酸激动剂的发现导致了谷氨酸受体亚型分类基础的建立。此外，我们还发现TI-233、tuberostemonine、MLV-208、MLV-5860和MLV-6976等化合物能显著阻断螯虾神经肌肉接头的谷氨酸反应。在这些化合物中，一些三亚甲基二胺衍生物显示出有效的抑制作用，对大鼠贫血性去大脑强直，药物诱导的小鼠震颤，和兔眼球震颤，这表明谷氨酸受体阻滞剂可能是有用的治疗中枢运动系统疾病。在本研究中，我们检查了三亚甲基二胺（尤其是MLV-6976）对中枢神经系统的影响。在大鼠贫血性去大脑强直中，MLV-6976以剂量依赖性方式抑制强直，剂量范围小于已确定的中枢作用肌松药。MLV-6976可轻微降低血压，但降低程度小于托哌酮。MLV-6976增强震颤诱导的震颤，但抑制骆驼蓬碱诱导的震颤。小鼠和大鼠的自发运动活动以及猫脊髓中的反射电位未受到MLV-6976的影响。MLV-6976以开放通道阻断方式抑制小龙虾神经肌肉接头处的谷氨酸反应。基于这些实验结果，讨论了MLV-6976作为中枢作用治疗剂的可能性。

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.