Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655

• Published in: Brain research bulletin Vol. 55; no. 3; pp. 387 - 391
• Main Authors: SZABADOS, Tamas, GIGLER, Gabor, GACSALYI, Istvan, GYERTYAN, Istvan, LEVAY, György
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Science 01.06.2001
• Subjects: Acoustic Stimulation; Animals; Anti-Anxiety Agents - pharmacology; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Benzodiazepines - pharmacology; Biological and medical sciences; Brain Ischemia - chemically induced; Brain Ischemia - physiopathology; Dose-Response Relationship, Drug; Electroshock; Magnesium Chloride; Male; Medical sciences; Mice; Mice, Inbred Strains; Neurology; Neuropharmacology; Neuroprotective Agents - pharmacology; Pharmacology. Drug treatments; Seizures - etiology; Seizures - physiopathology; Seizures - prevention & control; Survival Analysis; Time Factors; Vascular diseases and vascular malformations of the nervous system; Nervous system diseases; Rodentia; Cardiovascular disease; Anticonvulsant; Neuroprotective agent; Glutamate receptor; Cerebral disorder; Audiogenic epilepsy; Dose activity relation; Vascular disease; Vertebrata; Experimental disease; Mammalia; Ischemia; Mouse; Animal; Central nervous system disease; Benzodiazepine derivatives; Antagonist; Cerebrovascular disease; Comparative study; Brain (vertebrata)
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/s0361-9230(01)00516-0

GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine], a non-competitive AMPA [alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate] and kainate receptor antagonist and its two analogues, GYKI 53405 [1-(4-aminophenyl)-3-acetyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] and GYKI 53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] were investigated in two seizure models and in MgCl2 induced global cerebral ischaemia, as an acute neuroprotective model. The ED(50) values of GYKI 52466 for suppression of the tonic and clonic phases of sound-induced seizures were 3.6 and 4.3 mg/kg, respectively. The corresponding data for GYKI 53405 were 1.1 and 3.1 mg/kg, while ED(50) values of GYKI 53655 were 1.3 and 2.0 mg/kg, respectively. The inhibition of seizure evoked by maximal electroshock was also found to be remarkable: the ED(50) values of GYKI 52466 and its two analogues were 6.9, 2.6, and 2.2 mg/kg, respectively. All compounds prolonged the survival times in MgCl2 induced global cerebral ischaemia test in a dose-dependent fashion, with PD(50) (dose of 50% prolongation) values of 24.1, 8.3, and 8.2 mg/kg intraperitoneal, respectively. In audiogenic seizure model the duration of anticonvulsant action of 10 mg/kg GYKI 52466 and 5 mg/kg GYKI 53405, GYKI 53655 were examined, too. The effect of GYKI 52466 decreased to 50% after 2 h, while the analogues showed more than 80% seizure suppression 3 h after treatment. After 6 h the effect of GYKI 53655 decreased to zero, while the effect of GYKI 52466, remained on the 50% level.