Grondin R, Bédard P J, Britton D R, Shiosaki K
Department of Pharmacology, Faculty of Medecine, Laval University, Canada.
Neurology. 1997 Aug;49(2):421-6. doi: 10.1212/wnl.49.2.421.
The clinical utility of dopamine (DA) D1 receptor agonists in the treatment of Parkinson's disease (PD) is still unclear. The therapeutic use of selective DA D1 receptor agonists such as SKF-82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine hydrobromide) and A-77636 ([1R, 3S] 3-[1'-admantyl]-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzo pyran hydrochloride) seems limited because of their duration of action, which is too short for SKF-82958 (< 1 hr) and too long for A-77636 (> 20 hr, leading to behavioral tolerance). We therefore conducted the present acute dose-response study in four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed cynomolgus monkeys primed to exhibit levodopa-induced dyskinesias to evaluate the locomotor and dyskinetic effects on challenge with four doses (from 0.03 to 1.0 mg/kg) of A-86929 ([-]-[5aR,11bS]-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-+ ++azacyclopent-1- ena[c]phenathrene-9-10-diol), a selective and full DA D1-like receptor agonist with an intermediate duration of action. Levodopa and the DA D2-like receptor agonist, LY-171555 ([4aR-trans]-4,4a,5,6,7,8,8a,9-o-dihydro-5n-propyl-2H-pyrazo lo-3-4-quinoline hydrochloride) were also used for comparison. Acute administration of A-86929 was as efficacious in alleviating MPTP-induced parkinsonism as levodopa and LY-171555, but was less likely to reproduce the levodopa-induced dyskinesias in these animals than with either LY-171555 or subsequent challenge of levodopa. Selective stimulation of the DA D1 receptor may provide better integration of neural inputs transmitted to the internal segment of the globus pallidus (referred to as the basal ganglia output) compared with levodopa and selective DA D2 receptor agonist. Potent DA D1 receptor agents with an intermediate duration of efficacy such as A-86929 (approximately 4 hr at higher doses tested) are potential therapeutic tools in PD and merit further attention.
多巴胺（DA）D1受体激动剂在帕金森病（PD）治疗中的临床效用仍不明确。选择性DA D1受体激动剂，如SKF - 82958（6 - 氯 - 7,8 - 二羟基 - 3 - 烯丙基 - 1 - 苯基 - 2,3,4,5 - 四氢 - 1H - 3 - 苯并氮杂卓氢溴酸盐）和A - 77636（[1R, 3S] 3 - [1'-金刚烷基] - 1 - 氨基甲基 - 3,4 - 二氢 - 5,6 - 二羟基 - 1H - 2 - 苯并吡喃盐酸盐）的治疗用途似乎有限，因为它们的作用持续时间，对SKF - 82958来说太短（<1小时），对A - 77636来说太长（>20小时，导致行为耐受性）。因此，我们在四只经1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）处理、已引发左旋多巴诱导异动症的食蟹猴中进行了本次急性剂量反应研究，以评估四种剂量（0.03至1.0毫克/千克）的A - 86929（[-]-[5aR,11bS]-4,5,5a,6,7,11b - 六氢 - 2 - 丙基 - 3 - 硫杂 - 5 - 氮杂环戊 - 1 - 烯并[c]菲 - 9,10 - 二醇）（一种具有中等作用持续时间的选择性和完全DA D1样受体激动剂）激发后的运动和异动效应。左旋多巴和DA D2样受体激动剂LY - 171555（[4aR - 反式] - 4,4a,5,6,7,8,8a,9 - 八氢 - 5 - 正丙基 - 2H - 吡唑并[3,4 - b]喹啉盐酸盐）也用于比较。急性给予A - 86929在减轻MPTP诱导的帕金森症方面与左旋多巴和LY - 171555一样有效，但与LY - 171555或随后给予左旋多巴相比，在这些动物中诱发左旋多巴诱导的异动症的可能性较小。与左旋多巴和选择性DA D2受体激动剂相比，选择性刺激DA D1受体可能能更好地整合传递到苍白球内侧段（称为基底神经节输出）的神经输入。具有中等疗效持续时间的强效DA D1受体药物，如A - 86929（在测试的较高剂量下约为4小时），是PD治疗中的潜在工具，值得进一步关注。
