Novel alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonists of 2,3-benzodiazepine type: chemical synthesis, in vitro characterization, and in vivo prevention of acute neurodegeneration.
Under pathophysiological conditions, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor activation is considered to play a key role in several disorders of the central nervous system. In the search for AMPA receptor antagonists, the synthesis and pharmacological characterization of a series of novel compounds that are structurally related to GYKI 52466 (1), a well-known selective noncompetitive AMPA receptor antagonist, was performed. In vitro, 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638, 14a) antagonized the kainate-induced currents in cultured hippocampal neurons with an IC(50) of 3.4 microM in a noncompetitive fashion. When tested in a clinically predictive rat model of acute ischemic stroke, this noncompetitive AMPA receptor antagonist significantly reduced brain infarction, indicating that it is neuroprotective after permanent focal cerebral ischemia.
Schering AG, Berlin, Germany. bernd.elger@schering.de
Bernd
B
Elger
Andreas
A
Huth
Roland
R
Neuhaus
Eckard
E
Ottow
Herbert
H
Schneider
Bernd
B
Seilheimer
Lechoslaw
L
Turski
D000208:Acute Disease; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000150:complications; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology
C502816:2,3-dimethyl-6-phenyl-12H-(1,3)dioxolo(4,5-h)imidazo(1,2-c)(2,3)benzodiazepine; D004149:Dioxoles; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D001569:Benzodiazepines; D007608:Kainic Acid