D'Hooge R, Raes A, Hiramatsu M, Mori A, Van Bogaert P P, De Deyn P P
Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp (UIA), Belgium.
Arzneimittelforschung. 1998 Dec;48(12):1121-5.
The competitive N-methyl-D-aspartate (NMDA) antagonist DL-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 127910-31-0, 4-methyl-APPA, CGP 37849) and its ethyl ester (CAS 127910-32-1, CGP 39551) potently block NMDA-evoked whole-cell current on mouse spinal neurones in primary dissociated cell cultures with IC50 (+/- SE) values of 189 +/- 9 nmol/l (CGP 37849) and 2100 +/- 220 nmol/l (CGP 39551), respectively. The compounds dose-dependently blocked vestibular stimulation-induced convulsions in EL mice, 2 h after oral administration, with ED50 (95% CI) values of 135 (78-236) mumol/kg (CGP 37849) and 65 (45-94) mumol/kg (CGP 39551). In male Swiss albino mice, performance in the step-through passive avoidance procedure was dose-dependently impaired with ED50 (95% CI) values of 85 (56-157) mumol/kg (CGP 37849) and 27 (18-42) mumol/kg (CGP 39551). In addition performance of these animals in the rotarod test of motor coordination was impaired, 2 h after oral administration of CGP 39551, with an ED50 (95% CI) of 142 (100-201) mumol/kg. These findings demonstrate anticonvulsant activity in these potent NMDA antagonists after oral administration with CGP 39551 possessing greater relative potency. However, the unfavourable ratio of therapeutic dose versus dose inducing memory or motor impairment supports the prevailing notion that such adverse effects of the presently available compounds preclude the use of NMDA antagonists as long-term therapies.
竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂DL-2-氨基-4-甲基-5-膦酰基-3-戊烯酸（CAS 127910-31-0，4-甲基-APPA，CGP 37849）及其乙酯（CAS 127910-32-1，CGP 39551）能有效阻断原代解离细胞培养的小鼠脊髓神经元上NMDA诱发的全细胞电流，其IC50（±SE）值分别为189±9 nmol/L（CGP 37849）和2100±220 nmol/L（CGP 39551）。口服给药2小时后，这些化合物能剂量依赖性地阻断EL小鼠前庭刺激诱发的惊厥，其ED50（95%CI）值分别为135（78 - 236）μmol/kg（CGP 37849）和65（45 - 94）μmol/kg（CGP 39551）。在雄性瑞士白化小鼠中，穿梭箱被动回避试验中的表现呈剂量依赖性受损，其ED50（95%CI）值分别为85（56 - 157）μmol/kg（CGP 37849）和27（18 - 42）μmol/kg（CGP 39551）。此外，口服CGP 39551 2小时后，这些动物在转棒运动协调试验中的表现受损，其ED50（95%CI）为142（100 - 201）μmol/kg。这些发现表明，口服给药后这些强效NMDA拮抗剂具有抗惊厥活性，其中CGP 39551的相对效力更大。然而，治疗剂量与诱导记忆或运动损伤剂量的不利比例支持了目前普遍的观点，即现有化合物的此类不良反应使NMDA拮抗剂无法作为长期治疗药物使用。
