Unangst P C, Capiris T, Connor D T, Doubleday R, Heffner T G, MacKenzie R G, Miller S R, Pugsley T A, Wise L D
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1997 Dec 5;40(25):4026-9. doi: 10.1021/jm970422s.
The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar Ki values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 receptor binding selectivity were also identified. A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [3H]thymidine in D4-transfected CHO 10,001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity (intrinsic activity of 0-19% in comparison to quinpirole).
本文描述了一系列对多巴胺D4受体具有选择性亲和力的新型（芳氧基）烷基胺的发现。对目标化合物进行了测试，以检测其与在中国仓鼠卵巢（CHO）K-1细胞中表达的克隆人多巴胺D2、D3和D4受体亚型的结合情况。许多化合物对D4受体的结合表现出亚纳摩尔级的Ki值，对D2和D3受体具有若干100倍的选择性。还鉴定出了几种具有D3/D4受体结合选择性的化合物。讨论了该化学系列有限的构效关系研究。在一项促有丝分裂功能测定中，测量了测试化合物对D4转染的CHO 10,001细胞中[3H]胸腺嘧啶核苷细胞摄取的影响，并与全多巴胺激动剂喹吡罗的反应进行了比较。这些化合物的活性从完全拮抗剂到弱部分激动剂活性不等（与喹吡罗相比，内在活性为0-19%）。
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