Abstract:
:Glutamate is a potent candidate of the excitatory transmitter at the invertebrate NMJ and the synapse of the vertebrate CNS. But pharmacological studies have not been enough to prove that glutamate functions as an excitatory neurotransmitter. During the past 10 years, we have been studying the effects of various compounds which demonstrate the glutamate blocking action, but the glutamate responses are more effectively blocked by the drugs than the nerve-evoked synaptic response. A marked difference was revealed by TI-233, the minimum concentration of TI-233 on EJP being about a hundred times greater than the minimum threshold concentration on the glutamate-induced responses. The subsequent studies demonstrated that the action of TI-233 was able to be explained by the open channel block of the glutamate-activated ion-channel. The difference does not confute the hypothesis that glutamate is the natural transmitter substance at the crayfish NMJ, notwithstanding the fact that the action of the transmitter candidate on the postsynaptic membrane must be identical in every respect with that of the transmitter. Once something potentially useful has been found it is necessary to know not only what a substance does but how well it does it, so that comparisons can be made and better drugs discovered. Our first task therefore was to find a powerful glutamate blocker. Recently, as a result of synthesizing a series of compounds on the base of the structure-activity relationship in drug design, a series of compounds was found to reduce markedly glutamate responses at the crayfish NMJ and the mammalian central neurones at extremely low concentrations. In addition, a novel potent excitatory amino acid, acromelic acid, was found. This compound markedly excites the crayfish opener muscle and the mammalian central neurones. Agonists and antagonists have provided a very useful tool for neuroscience research, and findings of these new pharmacological tools will lead to progress in pharmacological studies to elucidate the function of glutamate in the body, in addition to other established compounds. The recent advances in our limited understanding of pharmacology of the glutamate receptor are discussed here.
journal_name
Prog Neurobioljournal_title
Progress in neurobiologyauthors
Shinozaki Hdoi
10.1016/0301-0082(88)90009-3subject
Has Abstractpub_date
1988-01-01 00:00:00pages
399-435issue
5eissn
0301-0082issn
1873-5118pii
0301-0082(88)90009-3journal_volume
30pub_type
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