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.
Elger
Bernd
B
Schering AG, Berlin, Germany. bernd.elger@schering.de
Huth
Andreas
A
Neuhaus
Roland
R
Ottow
Eckard
E
Schneider
Herbert
H
Seilheimer
Bernd
B
Turski
Lechoslaw
L
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