Claustre Y, Fage D, Zivkovic B, Scatton B
J Pharmacol Exp Ther. 1985 Feb;232(2):519-25.
6,7-Dihydroxy-2-dimethylaminotetralin (TL-99), N-n-propyl-3-(3-hydroxyphenylpiperidine [(+/-)-3-PPP], N-n-propylnorapomorphine and pergolide were evaluated for activity on a number of biochemical parameters that are presumed to indicate an agonist effect at dopamine (DA) autoreceptors (antagonism of the gamma-hydroxybutyrate-induced increase in dopa formation), at postsynaptic DA receptors (elevation of acetylcholine levels) or at both types of DA receptors (diminution of DA synthesis and homovanillic acid levels) in rat striatum. All four agents decreased striatal dopa accumulation (in the presence and in the absence of gamma-hydroxybutyrate). N-propylnorapomorphine, pergolide and TL-99 also reduced homovanillic acid levels and increased acetylcholine concentrations in striatum whereas (+/-)-3-PPP was inactive. The compounds were all more potent in diminishing dopa accumulation caused by gamma-hydroxybutyrate treatment than in increasing acetylcholine levels [(+/-)-3-PPP showing the highest dissociation] indicating a preferential agonist activity at DA autoreceptors. The relative selectivity of the compounds for DA autoreceptors and postsynaptic DA receptors was evaluated further by studying the antagonism by these drugs of the activation of striatal dopa formation (index of both DA autoreceptor and postsynaptic DA receptor stimulation) and tyrosine hydroxylase (index of postsynaptic DA receptor stimulation only) induced by haloperidol or reserpine. The DA agonists were all more potent in antagonizing the neuroleptic-induced increase in DA synthesis than in counteracting the drug-induced activation of tyrosine hydroxylase, with (+/-)-3PPP exhibiting the highest dissociation. The present results indicate that the DA agonists studied possess some selectivity for striatal DA autoreceptors, (+/-)-3-PPP being the most selective in this respect.
对6,7-二羟基-2-二甲基氨基四氢萘（TL-99）、N-正丙基-3-(3-羟基苯基)哌啶[（±）-3-PPP]、N-正丙基去甲阿扑吗啡和培高利特进行了评估，观察它们对一些生化参数的作用，这些参数被认为可表明其对大鼠纹状体中多巴胺（DA）自身受体（拮抗γ-羟基丁酸诱导的多巴形成增加）、突触后DA受体（乙酰胆碱水平升高）或两种类型DA受体（DA合成和高香草酸水平降低）的激动剂效应。所有这四种药物均降低了纹状体中的多巴积累（无论有无γ-羟基丁酸）。N-正丙基去甲阿扑吗啡、培高利特和TL-99还降低了纹状体中的高香草酸水平并增加了乙酰胆碱浓度，而（±）-3-PPP则无活性。这些化合物在减少γ-羟基丁酸处理引起的多巴积累方面比增加乙酰胆碱水平更有效[（±）-3-PPP表现出最大的差异]，表明其对DA自身受体具有优先激动剂活性。通过研究这些药物对氟哌啶醇或利血平诱导的纹状体多巴形成激活（DA自身受体和突触后DA受体刺激的指标）和酪氨酸羟化酶（仅突触后DA受体刺激的指标）的拮抗作用，进一步评估了这些化合物对DA自身受体和突触后DA受体的相对选择性。这些DA激动剂在拮抗抗精神病药物诱导的DA合成增加方面比抵消药物诱导的酪氨酸羟化酶激活更有效，（±）-3PPP表现出最大的差异。目前的结果表明，所研究的DA激动剂对纹状体DA自身受体具有一定的选择性，（±）-3-PPP在这方面是最具选择性的。
