Chapman A G, Nanan K, Williams M, Meldrum B S
Department of Clinical Neurosciences, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK.
Neuropharmacology. 2000 Jul 10;39(9):1567-74. doi: 10.1016/s0028-3908(99)00242-7.
The selective mGlu5 antagonists, MPEP, 2-methyl-6-phenylethynyl-pyridine, and SIB1893, (E)-6-methyl-2-styryl-pyridine, have been evaluated as antiepileptic drugs in DBA/2 mice and lethargic mice. Clonic seizures induced by the selective mGlu5 agonist, (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), 3 micromol intracerebroventricularly (i.c.v.), are potently suppressed by both compounds (MPEP, ED(50)=0.42 [0.28-0.62] mg/kg intraperitoneally (i.p.); SIB 1893 ED(50)=0.19 [0.11-0.33] mg/kg i.p. ). Clonic seizures induced by the mGlu1,5 agonist, 3, 5-dihydroxyphenylglycine (DHPG), 1.5 micromol i.c.v., are less potently suppressed by both compounds (MPEP, ED(50)=22 [13-38] mg/kg i.p., 110 [67-180] nmol i.c.v.; SIB1893, ED(50)=31 [18-54] mg/kg i.p. , 95 [82-110] nmol i.c.v.). Sound-induced seizures in DBA/2 mice are suppressed at 15 min by MPEP and SIB 1893 (MPEP ED(50) clonic seizures=18 [10-32] mg/kg i.p., 93 [69-125] nmol i.c.v.; tonic seizures=6.1 [4.5-8.3] mg/kg i.p., 46 [26-80] nmol i.c.v.; SIB 1893 ED(50) clonic seizures=27 [17-44] mg/kg i.p., 825 [615-1108] nmol i. c.v., tonic seizures=5.4 [3.4-8.6] mg/kg i.p., 194 [113-332] nmol i. c.v.). The ED(50) for MPEP for impaired rotarod performance is 128 [83-193] mg/kg i.p., at 15 min, i.e. a therapeutic index for sound-induced seizures of 5-20. In lethargic mice (lh/lh), a genetic absence model, MPEP, 50 mg/kg i.p., caused a marked reduction in the incidence of spontaneous spike-and-wave discharges. These selective antagonists of mGlu5 block seizures due to activation of mGlu5 at very low systemic doses. At rather higher doses they block convulsive and non-convulsive primary generalised seizures.
选择性代谢型谷氨酸受体5（mGlu5）拮抗剂2-甲基-6-苯基乙炔基吡啶（MPEP）和（E）-6-甲基-2-苯乙烯基吡啶（SIB1893）已在DBA/2小鼠和嗜睡小鼠中作为抗癫痫药物进行了评估。选择性mGlu5激动剂（R,S）-2-氯-5-羟基苯甘氨酸（CHPG），脑室内注射3微摩尔可诱发阵挛性癫痫发作，这两种化合物（MPEP，腹膜内注射半数有效量（ED(50)）=0.42[0.28 - 0.62]毫克/千克；SIB1893，ED(50)=0.19[0.11 - 0.33]毫克/千克腹膜内注射）均能有效抑制。mGlu1、5激动剂3,5-二羟基苯甘氨酸（DHPG），脑室内注射1.5微摩尔诱发的阵挛性癫痫发作，这两种化合物对其抑制作用较弱（MPEP，ED(50)=22[13 - 38]毫克/千克腹膜内注射，110[67 - 180]纳摩尔脑室内注射；SIB1893，ED(50)=31[18 - 54]毫克/千克腹膜内注射，95[82 - 110]纳摩尔脑室内注射）。MPEP和SIB1893可在15分钟时抑制DBA/2小鼠由声音诱发的癫痫发作（MPEP，阵挛性癫痫发作ED(50)=18[10 - 32]毫克/千克腹膜内注射，93[69 - 125]纳摩尔脑室内注射；强直性癫痫发作=6.1[4.5 - 8.3]毫克/千克腹膜内注射，46[26 - 80]纳摩尔脑室内注射；SIB1893，阵挛性癫痫发作ED(50)=27[17 - 44]毫克/千克腹膜内注射，825[615 - 1108]纳摩尔脑室内注射，强直性癫痫发作=5.4[3.4 - 8.6]毫克/千克腹膜内注射，194[113 - 332]纳摩尔脑室内注射）。MPEP对旋转棒性能受损的ED(50)为128[83 - 193]毫克/千克腹膜内注射，在15分钟时，即声音诱发癫痫发作的治疗指数为5 - 20。在嗜睡小鼠（lh/lh）（一种遗传性失神模型）中，腹膜内注射50毫克/千克的MPEP可显著降低自发性棘波和慢波放电的发生率。这些mGlu5选择性拮抗剂在非常低的全身剂量下就能阻断因mGlu5激活而导致的癫痫发作。在相对较高剂量时，它们能阻断惊厥性和非惊厥性原发性全身性癫痫发作。
