title: Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist.
abstract: GYKI 53784 or LY303070 [(-)1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine] belongs to a new family of 2,3-benzodiazepine compounds (also called homophtalazines) selective and non-competitive antagonists at alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These compounds include the original GYKI-52466, its more potent derivative GYKI 53655 and the active isomer of the latter, GYKI 53784. This review summarizes current knowledge of this novel AMPA antagonist: GYKI 53784. GYKI 53784 is the most potent of the compounds in the 2,3-benzodiazepine class, blocking AMPA receptor-mediated responses. In contrast to the compounds of the quinoxalinedione family, that block AMPA as well as kainate receptors, GYKI 53784 does not block the activation of kainate receptors. Furthermore, GYKI 53784 does not act at the same receptor site as positive AMPA modulators (i.e., cyclothiazide, BDP-12, 1-BCP or aniracetam). GYKI 53784 is a powerful neuroprotective agent in both in vitro and in vivo models of AMPA receptor-mediated excitotoxicity. In contrast to NMDA receptor antagonists, whose favorable clinical actions are compromised by important side effects such as the impairment of memory functions, the selective AMPA antagonist, GYKI 53784, may be of potential clinical value, both in acute (stroke and trauma) and chronic (Alzheimer's disease, epilepsy) neurological disorders.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000494:Allosteric Regulation; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D003056:Cochlear Nerve / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D018696:Neuroprotective Agents / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D001569:Benzodiazepines; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C118651:GYKI 53784