Unangst P C, Capiris T, Connor D T, 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 Aug 15;40(17):2688-93. doi: 10.1021/jm970170v.
The discovery of a series of chromeno[3,4-c]pyridin-5-ones 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. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.
本文描述了一系列对多巴胺D4受体具有选择性亲和力的色烯并[3,4-c]吡啶-5-酮的发现。对目标化合物进行了检测，以确定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。几种化合物对D4受体的结合显示出个位数纳摩尔的Ki值，对D2和D3受体具有数百倍的选择性。本文讨论了该系列化合物的有限构效关系（SAR）研究。在一项测量[3H]胸腺嘧啶核苷摄取的有丝分裂原测定中，目标化合物在D4受体上表现出拮抗剂至弱部分激动剂活性，内在活性范围为0%至35%。化合物6，3-苄基-8-甲基-1,2,3,4-四氢色烯并[3,4-c]吡啶-5-酮，当以10mg/kg口服给药时，可使大鼠脑海马体中的多巴（L-3,4-二羟基苯丙氨酸）合成增加84%，纹状体中增加10%。
