Donevan S D, Yamaguchi S, Rogawski M A
Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
J Pharmacol Exp Ther. 1994 Oct;271(1):25-9.
Block of AMPA (alpha-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 microM, respectively; the corresponding values for GYKI 53405 were 3.8 and 5.0 microM. 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 10(5) M-1 sec-1) compared with GYKI 52466 (1.6 x 10(5) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
在原代培养的大鼠海马神经元全细胞电压钳记录中，评估了非竞争性非N-甲基-D-天冬氨酸（AMPA/红藻氨酸）受体拮抗剂GYKI 52466 [1-(4-氨基苯基)-4-甲基-7,8-亚甲基二氧基-5H-2,3-苯并二氮杂卓]以及两种3-N-取代的3,4-还原GYKI 52466类似物对AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）和红藻氨酸电流的阻断作用。此外，还在最大电休克惊厥试验中以及在保护小鼠免受红藻氨酸诱发惊厥的试验中测定了这些类似物的活性。所测试的GYKI 52466类似物为3-N-甲基氨基甲酰基[GYKI 53655；1-(4-氨基苯基)-3-甲基氨基甲酰基-4-甲基-3,4-二氢-7,8-亚甲基二氧基-5H-2,3-苯并二氮杂卓]和3-N-乙酰基[GYKI 53405；1-(4-氨基苯基)-3-乙酰基-4-甲基-3,4-二氢-7,8-亚甲基二氧基-5H-2,3-苯并二氮杂卓]。GYKI 53655对AMPA和红藻氨酸诱发的电流产生浓度依赖性抑制，IC50值分别为1.1和1.5 microM；GYKI 53405的相应值为3.8和5.0 microM。作为AMPA电流的阻断剂，这些类似物的效力分别比母体GYKI 52466高8倍和2.3倍。动力学分析表明，与GYKI 52466（1.6×10⁵ M⁻¹ sec⁻¹）相比，两种3-N-取代类似物的结合速率增加（2.5 - 2.6×10⁵ M⁻¹ sec⁻¹）。GYKI 52466、GYKI 53405和GYKI 53655的解离速率与阻断效力的增加呈负相关（分别为2.9、1.7和0.6 sec⁻¹）。因此，3-N-取代类似物亲和力的增加与其结合增加和解离速率降低有关。（摘要截短为250字）
