Spadoni G, Balsamini C, Diamantini G, Tontini A, Tarzia G, Mor M, Rivara S, Plazzi P V, Nonno R, Lucini V, Pannacci M, Fraschini F, Stankov B M
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino, Italy.
J Med Chem. 2001 Aug 30;44(18):2900-12. doi: 10.1021/jm001125h.
Several indole analogues of melatonin (MLT) were obtained by moving the MLT side chain from C(3) to C(2) of the indole ring. Binding and in vitro functional assays were performed on cloned human MT1 and MT2 receptors, stably transfected in NIH3T3 cells. Quantitative structure-activity relationship studies showed that 4-methoxy-2-(N-acylaminomethyl)indoles, with a benzyl group in position 1, were selective MT2 antagonists and, in particular, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide (12) behaved as a pure antagonist at MT1 and MT2 receptors, with a 148-fold selectivity for MT2. We present a topographical model that suggests a lipophilic group, located out of the plane of the indole ring of MLT, as the key feature of the MT2 selective antagonists.
通过将褪黑素（MLT）的侧链从吲哚环的C(3)位移至C(2)位，获得了几种MLT的吲哚类似物。对稳定转染到NIH3T3细胞中的克隆人MT1和MT2受体进行了结合和体外功能测定。定量构效关系研究表明，在1位带有苄基的4-甲氧基-2-(N-酰基氨甲基)吲哚是选择性MT2拮抗剂，特别是N-[(1-对氯苄基-4-甲氧基-1H-吲哚-2-基)甲基]丙酰胺（12）在MT1和MT2受体上表现为纯拮抗剂，对MT2的选择性为148倍。我们提出了一个拓扑模型，该模型表明位于MLT吲哚环平面外的一个亲脂性基团是MT2选择性拮抗剂的关键特征。
