Parsons C G, Danysz W, Quack G, Hartmann S, Lorenz B, Wollenburg C, Baran L, Przegalinski E, Kostowski W, Krzascik P, Chizh B, Headley P M
Department of Pharmacology, Merz and Co., D-60318 Frankfurt am Main, Germany.
J Pharmacol Exp Ther. 1997 Dec;283(3):1264-75.
A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycineB). All compounds displaced [3H]MDL-105,519 binding to rat cortical membranes with IC50 values of between 90 nM and 3.6 microM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. The antagonism observed was typical for glycineB antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher concentrations (>100 microM) were required to antagonize alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They were potent, systemically active NMDA receptor antagonists in vivo against responses of single neurons in the rat spinal cord to microelectrophoretic application of NMDA with ID50 values in the low milligram per kilogram i.v. range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock-induced convulsions in mice with ED50 values ranging from 8 to 100 mg/kg i.p. The duration of anticonvulsive action was rather short but was prolonged by the organic acid transport inhibitor probenecid (200 mg/kg). The agents tested represent a novel class of systemically active glycineB antagonists with greatly improved bioavailability.
对一系列新型三环吡啶并酞嗪二酮衍生物进行了测试,以考察其对N-甲基-D-天冬氨酸(NMDA)受体(甘氨酸B)的士的宁不敏感调节位点的拮抗作用。所有化合物均能取代[3H]MDL-105,519与大鼠皮层膜的结合,IC50值在90 nM至3.6 μM之间。在膜片钳实验中,这些相同的化合物能拮抗培养的海马神经元对NMDA(200 μM,甘氨酸1 μM)的稳态内向电流反应,IC50值为0.14至13.8 μM。观察到的拮抗作用是甘氨酸B拮抗剂的典型特征,即它们诱导脱敏,且其作用不依赖于使用情况或电压。此外,甘氨酸浓度的增加能够降低它们的表观效力。拮抗α-氨基-3-羟基-5-甲基-4-异恶唑丙酸诱导的电流需要更高的浓度(>100 μM)。它们是有效的、具有全身活性的NMDA受体拮抗剂,在体内可对抗大鼠脊髓单个神经元对微电泳施加NMDA的反应,静脉注射ID50值在每千克低毫克范围内。它们还能抑制小鼠的戊四氮、NMDA和最大电休克诱导的惊厥,腹腔注射ED50值范围为8至100 mg/kg。抗惊厥作用的持续时间相当短,但可被有机酸转运抑制剂丙磺舒(200 mg/kg)延长。所测试的这些药物代表了一类新型的具有全身活性的甘氨酸B拮抗剂,其生物利用度有了极大提高。