Leiden/Amsterdam Center of Drug Research-LACDR, Amsterdam Institute for Molecules Medicines and Systems-AIMMS, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
J Med Chem. 2012 Oct 25;55(20):8603-14. doi: 10.1021/jm300801u. Epub 2012 Oct 12.
The 5-HT₃ receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT₃ hit fragment. Here we describe the synthesis and structure-activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT₃ R affinity using a [³H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pK(i) > 10) for the 5-HT₃ receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT₃ ligands and is used for ligand-receptor binding mode prediction using homology modeling and in silico docking approaches.
5-HT₃ 受体是一种五聚体配体门控离子通道（pLGIC），是一个重要的治疗靶点。在最近的一项片段筛选中，6-氯-N-甲基-2-(4-甲基-1,4-二氮杂环庚烷-1-基)喹唑啉-4-胺（1）被鉴定为 5-HT₃ 命中片段。在这里，我们描述了一系列（异）喹啉和喹唑啉化合物的合成和构效关系（SAR），这些化合物是通过[³H]granisetron 置换测定法合成并筛选 5-HT₃ R 亲和力的。这些研究发现了几个高亲和力配体，其中化合物 22 对 5-HT₃ 受体表现出最高的亲和力（pK(i) > 10）。观察到的 SAR 与 5-HT₃ 配体的既定药效基团模型一致，并用于同源建模和计算对接方法进行配体-受体结合模式预测。
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