Castriconi Federica, Paolino Marco, Giuliani Germano, Anzini Maurizio, Campiani Giuseppe, Mennuni Laura, Sabatini Chiara, Lanza Marco, Caselli Gianfranco, De Rienzo Francesca, Menziani Maria Cristina, Sbraccia Maria, Molinari Paola, Costa Tommaso, Cappelli Andrea
Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
Rottapharm Madaus, Via Valosa di Sopra 9, 20052 Monza, Italy.
Eur J Med Chem. 2014 Jul 23;82:36-46. doi: 10.1016/j.ejmech.2014.05.015. Epub 2014 May 5.
A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a-g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor-G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptor-G protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor.
通过应用构象限制方法，从柔性2-甲氧基喹啉化合物7a、b设计了一小系列血清素5-HT4受体配体。合成了配体7a、b以及相应的构象受限类似物8a - g，并通过测量结合亲和力以及促进或抑制受体 - G蛋白偶联的能力来研究它们与5-HT4受体的相互作用。酯衍生物7a和构象受限化合物8b被证明是最有趣的化合物，显示出与参比配体西沙必利(1)和RS - 23,597 - 190(4)相似的纳摩尔级5-HT4R亲和力。通过对接研究，根据柔性7a和构象受限8b在结合模式上的高度相似性，对该结果进行了合理说明。通过评估受体 - G蛋白偶联来确定一些选定配体的内在活性，所获得的结果表明取代基的性质和位置在这些配体与其受体的相互作用中起着关键作用。
