Spadoni G, Balsamini C, Diamantini G, Di Giacomo B, Tarzia G, Mor M, Plazzi P V, Rivara S, Lucini V, Nonno R, Pannacci M, Fraschini F, Stankov B M
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino, Italy.
J Med Chem. 1997 Jun 20;40(13):1990-2002. doi: 10.1021/jm960651z.
The design, synthesis, and biological profile of several indole melatonin analogues with a conformationally restricted C3 amidoethane side chain are presented. Examination of the accessible conformations of the melatonin side chain led us to explore some of its fully or partially restricted analogues, 2-12, the binding affinity values of which were utilized to gain further insight on the melatonin binding site. Two pharmacophoric models have been devised for melatonin and the active compounds by conformational analysis and superimposition performed using the DISCO program. In these models, the melatonin side chain can adopt a gauche/anti conformation out of the indole plane. Another contribution of this study regards the observation of a possible binding point interaction around the C2 position of the indole, as suggested by the remarkably increased binding affinity observed in the C2-substituted analogues 6 and 9 and especially in the more rigid analogue 5. The biological activity and the efficacy of the new compounds were tested by measuring the inhibition of the forskolin-stimulated cAMP accumulation and the GTP gamma S index. Both analyses demonstrated that all of the compounds were full agonists with the exception of 4 and 9, which showed a slight reduction in efficacy and would seem to be partial agonists.
本文介绍了几种具有构象受限的C3氨基乙烷侧链的吲哚褪黑素类似物的设计、合成及生物学特性。对褪黑素侧链可及构象的研究促使我们探索其一些完全或部分受限的类似物（2-12），利用这些类似物的结合亲和力值来进一步深入了解褪黑素结合位点。通过使用DISCO程序进行构象分析和叠加，为褪黑素及活性化合物设计了两种药效团模型。在这些模型中，褪黑素侧链可在吲哚平面外采取 gauche/anti 构象。本研究的另一个贡献在于观察到吲哚C2位置周围可能存在结合点相互作用，这由C2取代类似物6和9，尤其是更刚性的类似物5中显著增加的结合亲和力所表明。通过测量对福斯高林刺激的cAMP积累的抑制作用和GTPγS指数来测试新化合物的生物活性和功效。两项分析均表明，除4和9外，所有化合物均为完全激动剂，4和9的功效略有降低，似乎为部分激动剂。
