Chapman A G, Graham J L, Patel S, Meldrum B S
Department of Neurology, Institute of Psychiatry, De Crespigny Park, London, England.
Epilepsia. 1991 Jul-Aug;32(4):578-87. doi: 10.1111/j.1528-1157.1991.tb04695.x.
Two novel N-methyl-D-aspartate (NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid CPG 37849 and the corresponding 1-ethyl ester CGP 39551, were tested as anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice, CGP 37849 is more potent than CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50 CGP 37849, 35.2 mumol/kg; ED50 CGP 39551, 28.1 mumol/kg). The time course of action of CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against clonic seizures for 48 h. Protection provided by other NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic acid 1-ethyl ester 3 h, 4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) 4 h, and CGP 37849 4 h. After oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (CGP 37849) and 4.0-6.1 for 24 h (CGP 39551). After i.p. administration, the TI values are CGP 37849 at 1 h 2.4, and at 3 h 20.0, CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced myoclonus for at least 285 min, with severe side effects at the highest dose tested. CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)
两种新型N-甲基-D-天冬氨酸（NMDA）拮抗剂，DL-(E)-2-氨基-4-甲基-5-膦酰基-3-戊烯酸（CPG 37849）及其相应的1-乙酯（CGP 39551），在DBA/2小鼠和光敏性塞内加尔狒狒（豚尾狒狒）中作为抗惊厥药进行了测试。在DBA/2小鼠中，当脑室内（i.c.v.）或腹腔内（i.p.）给药时，CGP 37849比CGP 39551更有效（60分钟时抑制阵挛性发作的ED50：i.c.v.分别为0.038和0.21 nmol；i.p.分别为3.40和19.1 μmol/kg）。当在小鼠中口服给药时，这两种化合物效力大致相当（CGP 37849的ED50为35.2 μmol/kg；CGP 39551的ED50为28.1 μmol/kg）。CGP 39551的作用时间过程异常延长：腹腔注射42 μmol/kg可预防阵挛性发作48小时。其他NMDA拮抗剂在小鼠中提供的保护持续时间要短得多：2-氨基-5-膦酰基戊酸（AP5）为1小时，2-氨基-7-膦酰基庚酸（AP7）为4小时，2-氨基-7-膦酰基庚酸1-乙酯为3小时，4-(3-膦酰基丙基)-2-哌嗪羧酸（CPP）为2小时，顺式-4-(膦酰基甲基)-2-哌啶羧酸（CGS 19755）为4小时，CGP 37849为4小时。口服给药后，治疗指数（TI = 旋转棒性能的ED50值与抗惊厥保护的ED50值之比）在3小时内（CGP 37849）保持相对恒定，为5.9 - 7.2，在24小时内（CGP 39551）为4.0 - 6.1。腹腔注射后，TI值在1小时时CGP 37849为2.4，在3小时时为20.0；CGP 39551在1小时时为2.3，在3小时时为7.1，在24小时时为3.6。在狒狒中，静脉注射（i.v.）48 - 191 μmol/kg剂量 的CGP 37849可抑制光诱导的肌阵挛至少285分钟，在测试的最高剂量时有严重副作用。静脉注射169 - 675 μmol/kg剂量的CGP 39551仅在测试的最高剂量时显示出微弱的抗惊厥活性（伴有严重副作用）。口服48 - 96 μmol/kg的CGP 37849在给药后4小时内未能预防光诱导的肌阵挛，但口服191 μmol/kg（40 mg/kg）在24小时后可完全抑制癫痫发作。另一方面，口服169 μmol/kg（40 mg/kg）的CGP 39551在4小时时可完全抑制癫痫发作活动，抗惊厥作用持续时间更长（2 - 3天）。（摘要截选至40字）
