Merchant K M, Gill G S, Harris D W, Huff R M, Eaton M J, Lookingland K, Lutzke B S, Mccall R B, Piercey M F, Schreur P J, Sethy V H, Smith M W, Svensson K A, Tang A H, Vonvoigtlander P F, Tenbrink R E
CNS Diseases Research, Pharmacia and Upjohn, Inc., Kalamazoo, Michigan, USA.
J Pharmacol Exp Ther. 1996 Dec;279(3):1392-403.
Dopamine D2-like receptors play an important role in the pharmacotherapy of psychotic disorders. Molecular and cellular techniques have identified distinct gene products (D2-long, D2-short, D3 and D4) displaying the D2 receptor pharmacology. However, the contribution of each subtype in antipsychotic effects of or their physiological role remain unclear. Here we describe the pharmacological effects of a selective D4 antagonist, U-101387. U-101387 displayed moderately high affinity (Ki = 10 nM) and selectivity for the dopamine D4.2 receptor expressed in clonal cell lines. It lacked measurable affinity for not only other dopamine receptors but also noradrenalin, serotonin and histamine receptor families (Ki > 2000 nM). It fully and dose-dependently antagonized quinpirole-induced cAMP inhibition (without producing any effect by itself) in stably transfected cells. U-101387 also displayed excellent oral bioavailability, brain penetration and other pharmacokinetic characteristics. Unlike classical neuroleptics (e.g., haloperidol), U-101387 neither blocked acute behavioral effects of amphetamine or apomorphine nor did it alter spontaneous locomotion by itself. Additionally, U-101387 was without effect in behavioral and biochemical tests predictive of extrapyramidal and neuroendocrine side effects. Consistent with the lack of autoreceptor function of D4, acute administration of U-101387 failed to alter dopamine neuronal firing by itself or reverse the inhibition produced by dopamine agonists and to affect monoamine turnover in areas innervated by the mesencephalic or hypothalamic dopamine neurons. However, U-101387 potently induced c-fos mRNA expression in the infralimbic/ventral prelimbic cortex to a level similar to that produced by the atypical antipsychotic, clozapine. This is consistent with the predominantly cortical distribution of the D4 receptor. Taken together, these results demonstrate that the D4-selective antagonist, U-101387, produces effects that are distinct from those of the nonselective D2 antagonists as well as D3-preferring agents. U-101387 offers a unique tool to understand the role of dopamine D4 receptors in diseases involving central dopamine systems.
多巴胺D2样受体在精神障碍的药物治疗中发挥着重要作用。分子和细胞技术已鉴定出具有D2受体药理学特性的不同基因产物（D2长型、D2短型、D3和D4）。然而，各亚型在抗精神病作用中的贡献或其生理作用仍不清楚。在此，我们描述了一种选择性D4拮抗剂U-101387的药理作用。U-101387对克隆细胞系中表达的多巴胺D4.2受体表现出中等程度的高亲和力（Ki = 10 nM）和选择性。它不仅对其他多巴胺受体，而且对去甲肾上腺素、5-羟色胺和组胺受体家族均缺乏可测量的亲和力（Ki > 2000 nM）。在稳定转染的细胞中，它能完全且剂量依赖性地拮抗喹吡罗诱导的cAMP抑制（自身无任何作用）。U-101387还表现出优异的口服生物利用度、脑渗透性和其他药代动力学特性。与经典抗精神病药物（如氟哌啶醇）不同，U-101387既不阻断苯丙胺或阿扑吗啡的急性行为效应，自身也不改变自发运动。此外，在预测锥体外系和神经内分泌副作用的行为和生化试验中，U-101387无作用。与D4缺乏自身受体功能一致，急性给予U-101387自身不会改变多巴胺神经元放电，也不能逆转多巴胺激动剂产生的抑制作用，且不影响中脑或下丘脑多巴胺神经元支配区域的单胺代谢。然而，U-101387能强力诱导边缘下/腹侧前额叶皮质中的c-fos mRNA表达，使其达到与非典型抗精神病药物氯氮平相似的水平。这与D4受体主要分布于皮质一致。综上所述，这些结果表明，D4选择性拮抗剂U-101387产生的效应不同于非选择性D2拮抗剂以及偏向D3的药物。U-101387为理解多巴胺D4受体在涉及中枢多巴胺系统的疾病中的作用提供了一个独特的工具。
