A68930：一种对多巴胺D1受体具有选择性的强效激动剂。

A68930: a potent agonist selective for the dopamine D1 receptor.

作者信息

DeNinno M P, Schoenleber R, MacKenzie R, Britton D R, Asin K E, Briggs C, Trugman J M, Ackerman M, Artman L, Bednarz L

机构信息

Neuroscience Research Division, Abbott Laboratories, Abbott Park, IL 60064.

出版信息

Eur J Pharmacol. 1991 Jun 25;199(2):209-19. doi: 10.1016/0014-2999(91)90459-4.

DOI:10.1016/0014-2999(91)90459-4

PMID:1683288

Abstract

A68930, (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent (EC50 = 2.5 nM), partial (intrinsic activity = 66% of dopamine) agonist in the fish retina dopamine-sensitive adenylate cyclase model of the D1 dopamine receptor. In the rat caudate-putamen model of the D1 dopamine receptor, A68930 is a potent (EC50 = 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3920 nM) full agonist in a biochemical model of the dopamine D2 receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the dopamine D1 receptor. A68930 also displays weak alpha 2-agonist activity but the molecule is virtually inactive at the alpha 1- and beta-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (greater than 20 h) contralateral turning that is antagonized by dopamine D1 receptor selective doses of SCH 23390 but not by D2 receptor selective doses of haloperidol. In this lesioned rat model, A68930 increases 2-deoxyglucose accumulation in the lesioned substantia nigra, pars reticulata. When tested in normal rats, A68930 elicits hyperactivity and, at higher doses, produces a forelimb clonus.

摘要

A68930，即（1R，3S）-1-氨甲基-5,6-二羟基-3-苯基异苯并二氢吡喃盐酸盐，在鱼类视网膜多巴胺敏感腺苷酸环化酶模型中是一种强效（EC50 = 2.5 nM）、部分（内在活性为多巴胺的66%）激动剂，作用于D1多巴胺受体。在D1多巴胺受体的大鼠尾状核-壳核模型中，A68930是一种强效（EC50 = 2.1 nM）的完全激动剂。相比之下，在多巴胺D2受体的生化模型中，A68930是一种弱得多（EC50 = 3920 nM）的完全激动剂。分子中3-苯基取代基的取向对于分子对多巴胺D1受体的亲和力和选择性至关重要。A68930还表现出较弱的α2激动剂活性，但该分子在α1和β肾上腺素受体上几乎无活性。在患有黑质-新纹状体神经元单侧6-OHDA损伤的大鼠中进行测试时，A68930引发长时间（超过20小时）的对侧旋转，这种旋转可被多巴胺D1受体选择性剂量的SCH 23390拮抗，但不能被D2受体选择性剂量的氟哌啶醇拮抗。在这种损伤大鼠模型中，A68930增加了损伤的黑质网状部中2-脱氧葡萄糖的积累。在正常大鼠中进行测试时，A68930引发多动，且在较高剂量时会产生前肢阵挛。