Strychnine-insensitive glycine site antagonists attenuate a cardiac arrest-induced movement disorder.
Male Sprague-Dawley rats underwent experimentally induced cardiac arrest and resuscitation, subsequently exhibiting involuntary jerking movements (myoclonus) with salient features similar to the human form of the disorder. The novel strychnine-insensitive glycine site antagonists ACEA-1011 (5-chloro-7-trifluoromethyl-1,2,3,4-tetrahydroquinoxaline-2,3,-dio ne) and ACEA-1021 (5-nitro-6,7-dichloro-quinoxalinedione) significantly attenuated the myoclonus in cardiac-arrested rats. (+)-HA-966, (+/-)-HA-966 (3-amino-1-hydroxy-2-pyrrolidinone), and felbamate (2-phenyl-1,3-propanediol dicarbamate) were also effective. Although the drugs vary in their selectivity for strychnine-insensitive glycine sites, they all possess antagonist activity at these sites. Vehicle injections (saline, dimethyl sulfoxide, water) were without effect and no obvious side effects were observed with any of the ligands tested in this study. Since hyperexcitability in the central nervous system is thought to underlie myoclonus, the attenuation of excitatory amino acid neurotransmission through antagonism of strychnine-insensitive glycine sites provides a logical mechanism of action for the antimyoclonic effects observed herein.
Matsumoto
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Department of Neurology, University of California Irvine 92717, USA.
Nguyen
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Truong
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D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D016887:Cardiopulmonary Resuscitation; D002490:Central Nervous System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000078328:Felbamate; D006323:Heart Arrest / Q000150:complications* / Q000188:drug therapy; D008297:Male; D009207:Myoclonus / Q000188:drug therapy* / Q000209:etiology; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013331:Strychnine / Q000494:pharmacology
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D011760:Pyrrolidinones; D011810:Quinoxalines; D018009:Receptors, Glycine; C082999:ACEA 1011; C092062:licostinel; C001369:1-hydroxy-3-amino-2-pyrrolidone; D013331:Strychnine; D000078328:Felbamate