The ES-242s, novel N-methyl-D-aspartate antagonists of microbial origin, interact with both the neurotransmitter recognition site and the ion channel domain.
ES-242-1 approximately 5 are novel microbial bioxanthracenes which do not contain nitrogen. The ES-242s inhibited the binding of [3H]TCP and [3H]CGS19755 to the N-methyl-D-aspartate (NMDA) receptor complex. They had no effect on the binding of the specific ligands for the non-NMDA receptor. The biochemical and pharmacological properties of ES-242-1 were fully examined since it is the most potent of the five compounds. ES-242-1 is highly specific for the NMDA receptor; it has no effect on other receptors. Kinetic analyses indicated that ES-242-1 inhibited the binding of [3H]TCP and [3H]CGS19755 in a competitive manner, respectively, suggesting that ES-242-1 interacts with both the transmitter recognition site and the channel domain. ES-242-1 selectively inhibited NMDA-induced Ca2+ influx in primary cultures of mouse hippocampal neurons. ES-242-1 also specifically blocked the increase in cyclic GMP accumulation induced by NMDA or L-glutamate in rat cerebellar slices. In a concentration range of 0.1-1.0 microM, ES-242-1 was as potent as MK-801 in preventing glutamate-induced neurotoxicity in primary cultures of mouse hippocampal neurons. These results show that ES-242-1 is a potent and specific antagonist for the NMDA receptor. The antagonistic properties of the ES-242s appear to be due to a novel mechanism of action at the NMDA receptor.
Toki
S
S
Tokyo Research Laboratories, Kyowa Hakko Kogyo Company, Limited, Japan.
Tsukuda
E
E
Nozawa
M
M
Nonaka
H
H
Yoshida
M
M
Matsuda
Y
Y
D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D007473:Ion Channels / Q000187:drug effects*; D007700:Kinetics; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D010875:Pipecolic Acids / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism
D007473:Ion Channels; D018377:Neurotransmitter Agents; D010875:Pipecolic Acids; D011714:Pyrans; D016194:Receptors, N-Methyl-D-Aspartate; C073561:ES 242-1; C053672:selfotel; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C012058:tenocyclidine; D006152:Cyclic GMP; D010622:Phencyclidine; D002118:Calcium