title: Stereoselective effects-of 2,3-benzodiazepines in vivo: electrophysiology and neuroprotection studies.
abstract: The stereoselectivity and potency of 3N-substituted 2,3-benzodiazepines were examined in vivo against excitation of spinal neurones induced by electrophoretic ejection of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate in anaesthetised rats. AMPA receptor antagonist activity resided in the (-) isomers, LY300164 and LY303070, which were effective given electrophoretically, intravenously (2.5-5 mg/kg) or orally (10 mg/kg). The same stereoselectivity was observed in neuroprotection studies. Thus, systemic administration of the (-) isomer, but not the (+) isomer, of these 2,3-benzodiazepines before or immediately after bilateral carotid artery occlusion in the gerbil was neuroprotective. For example, 10 mg/kg of LY300164 intraperitoneally or orally provided survival of up to 25% of hippocampal CA1 neurones.
authors.affiliation: Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, U.K.
authors.forename: D
authors.initials: D
authors.lastname: Lodge
authors.forename: A
authors.initials: A
authors.lastname: Bond
authors.forename: M J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: C A
authors.initials: CA
authors.lastname: Hicks
authors.forename: M G
authors.initials: MG
authors.lastname: Jones
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D007536:Isomerism; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000502:physiology* / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D001569:Benzodiazepines; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid