Caprathe B W, Jaen J C, Wise L D, Heffner T G, Pugsley T A, Meltzer L T, Parvez M
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1991 Sep;34(9):2736-46. doi: 10.1021/jm00113a010.
A series of rigid tricyclic analogues of the dopamine (DA) agonist PD 118440 [4-(1,2,5,6-tetrahydro-1-propyl-3-pyridinyl)-2-thiazolamine] was synthesized and evaluated for dopaminergic activity and DA autoreceptor selectivity. (R)-(+)-6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo[4,5-f]quinolin+ ++-2-amine [+)-6) was identified as the most selective DA autoreceptor agonist from this group of compounds. It inhibited spontaneous locomotor activity (LMA) in rodents, reversed the gamma-butyrolactone (GBL) induced accumulation of rat striatal DOPA and inhibited brain DA neuronal firing, all suggestive of direct DA autoreceptor agonist activity. However, (+)-6 is not completely free of postsynaptic DA activity, as evidenced by its stimulation of LMA in rats at high doses and its ability to produce stereotypy. On the other hand, (-)-6 appears to be a weak partial DA agonist with some effects on brain DA synthesis only at high doses. Like other DA autoreceptor agonists and DA antagonists, (+)-6 inhibited Sidman conditioned avoidance in squirrel monkeys, a test predictive of clinical antipsychotic activity. However, unlike classical antipsychotics, (+)-6 did not induce dystonias in haloperidol-sensitized squirrel monkeys, suggesting a minimal propensity toward extrapyramidal side effects (EPS).
合成了一系列多巴胺（DA）激动剂PD 118440 [4-(1,2,5,6-四氢-1-丙基-3-吡啶基)-2-噻唑胺]的刚性三环类似物，并对其多巴胺能活性和DA自身受体选择性进行了评估。(R)-(+)-6-丙基-4,5,5a,6,7,8-六氢噻唑并[4,5-f]喹啉-2-胺[(+)-6]被确定为该组化合物中最具选择性的DA自身受体激动剂。它抑制啮齿动物的自发运动活动（LMA），逆转γ-丁内酯（GBL）诱导的大鼠纹状体多巴积累，并抑制脑DA神经元放电，所有这些都表明其具有直接的DA自身受体激动剂活性。然而，(+)-6并非完全没有突触后DA活性，高剂量时它对大鼠LMA的刺激以及产生刻板行为的能力就证明了这一点。另一方面，(-)-6似乎是一种弱的部分DA激动剂，仅在高剂量时对脑DA合成有一些影响。与其他DA自身受体激动剂和DA拮抗剂一样，(+)-6抑制松鼠猴的西德曼条件性回避反应，这是一种预测临床抗精神病活性的试验。然而，与经典抗精神病药物不同的是，(+)-6在氟哌啶醇致敏的松鼠猴中不会诱发肌张力障碍，这表明其发生锥体外系副作用（EPS）的倾向极小。
