Kohno Y, Fukuzaki K, Kitahara K, Koja T
Product Management Department, Nippon Boehringer Ingelheim Co., Ltd., Kawanishi, Japan.
Eur J Pharmacol. 1997 Jan 29;319(2-3):197-205. doi: 10.1016/s0014-2999(96)00862-x.
The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.
他利克索（6-烯丙基-2-氨基-5,6,7,8-四氢-4H-噻唑并[4,5-d]氮杂䓬二盐酸盐，B-HT 920 CL2，多麦可）是一种非麦角类多巴胺D2受体激动剂，具有α2-肾上腺素能受体激动和5-HT3受体拮抗特性。本研究在腹内侧被盖区单侧损伤的猴子中检测了他利克索的抗震颤活性。他利克索剂量依赖性地抑制震颤，皮下注射和口服给药的半数有效量（ED50）分别为34微克/千克和84微克/千克。他利克索产生抗震颤作用的剂量远低于麦角类多巴胺受体激动剂溴隐亭（2-溴-α-麦角隐亭甲磺酸盐，ED50；2.5毫克/千克，皮下注射），且他利克索与左旋多巴（3,4-二羟基苯丙氨酸）联合使用具有协同作用。在腹内侧被盖区损伤的猴子中，产生抗震颤作用剂量的他利克索不会引起催吐行为，但有镇静作用。相反，给予溴隐亭的猴子在观察到抗震颤作用时会出现口腔运动、流涎和呕吐，但在所研究的任何剂量下均未出现明显的镇静行为。在重复给予他利克索（皮下注射每日剂量50微克/千克，共21天）期间，抗震颤作用的程度和持续时间没有变化，但镇静作用的程度和持续时间逐渐降低。他利克索的抗震颤作用可被舒必利显著抑制，但不受SCH 23390（7-氯-2,3,4,5-四氢-3-甲基-5-苯基-1H-3-苯并氮杂䓬-7-醇）或育亨宾抑制，而镇静作用则被舒必利和育亨宾抑制。他利克索的主要代谢产物没有抗震颤或镇静作用。这些结果表明，他利克索通过选择性刺激多巴胺D2受体发挥其抗震颤活性。
