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

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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.