Non-N-methyl-D-aspartate receptor antagonism by 3-N-substituted 2,3- benzodiazepines: Relationship to anticonvulsant activity

S. D. Donevan, S. I. Yamaguchi, Michael A Rogawski

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94 Scopus citations


Block of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) and kainate currents by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8- methylenedioxy-5H-2,3-benzodiazepine], a noncompetitive non-N-methyl-D- aspartate (AMPA/kainate) receptor antagonist, and two 3-N-substituted 3,4- reduced GYKI 52466 analogs was assessed in whole cell voltage-clamp recordings from cultured rat hippocampal neurons. In addition, the activity of the analogs was determined in the maximal electroshock seizure test and for protection against kainate-induced seizures in mice. The analogs of GYKI 52466 tested were the 3-N-methylcarbamyl [GYKI 53655; 1-(4-aminophenyl)-3- methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] and the 3-N-acetyl [GYKI 53405; 1-(4-aminophenyl)-3-acetyl-4-methyl-3,4- dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine]. GYKI 53655 produced a concentration-dependent inhibition of AMPA- and kainate-induced currents with IC50 values of 1.1 and 1.5 μM, respectively; the corresponding values for GYKI 53405 were 3.8 and 5.0 μM. As blockers of AMPA currents, the analogs were 8- and 2.3-fold, respectively, more potent than the parent GYKI 52466. Kinetic analyses indicated increased association rates for the two 3-N- substituted analogs (2.5-2.6 x 105 M-1 sec-1) compared with GYKI 52466 (1.6 x 105 M-1 sec-1). The dissociation rates of GYKI 52466, GYKI 53405 and GYKI 53655 were inversely correlated with increasing blocking potency (2.9, 1.7 and 0.6 sec-1, respectively). Thus, the increased affinity of the 3-N-substituted analogs relates to their increased binding and decreased unbinding rates. In anticonvulsant testing in vivo, GYKI 53655 and GYKI 53405 had ED50 values against kainate (32 mg/kg s.c.) seizures of 4.6 and 7.5 mg/kg i.p., compared with 8.4 mg/kg for GYKI 52466. The corresponding values in the maximal electroshock seizure test were 4.6 and 5.9 mg/kg, compared with 11.8 mg/kg for GYKI 52466. The rank order of potencies of the three compounds in vivo corresponds with their in vitro potencies, supporting the view that the anticonvulsant activity is related to blockade of non-N- methyl-D-aspartate receptors.

Original languageEnglish (US)
Pages (from-to)25-29
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology


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