Van Tol H H, Bunzow J R, Guan H C, Sunahara R K, Seeman P, Niznik H B, Civelli O
Department of Pharmacology, University of Toronto, Ontario, Canada.
Nature. 1991 Apr 18;350(6319):610-4. doi: 10.1038/350610a0.
Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.
多巴胺受体属于G蛋白偶联受体家族。基于这些受体之间的同源性，已克隆出三种不同的多巴胺受体（D1、D2、D3）。多巴胺受体是用于治疗精神运动障碍（如帕金森病和精神分裂症）的药物的主要靶点。在治疗社交退缩和难治性精神分裂症患者时，氯氮平是最常用的抗精神病药物之一，因为它不会引起迟发性运动障碍。然而，氯氮平与D2和D3的结合解离常数是其在血浆水中治疗性游离浓度的4至30倍。这一观察结果表明存在对氯氮平更敏感的其他类型多巴胺受体。在此，我们报告了一个编码此类受体（D4）的基因的克隆。D4受体基因与人类多巴胺D2和D3受体基因具有高度同源性。该受体的药理学特性与D2和D3受体相似，但其对氯氮平的亲和力高一个数量级。识别和表征这个氯氮平神经安定位点可能对新型药物的设计有用。
