Dipartimento di Scienze degli Alimenti e del Farmaco , Università degli Studi di Parma , Parco Area delle Scienze 27/A , I-43124 Parma , Italy.
Institut de Recherches Servier , 125 Chemin de Ronde , F-78290 Croissy sur Seine , France.
J Med Chem. 2018 Apr 26;61(8):3726-3737. doi: 10.1021/acs.jmedchem.8b00359. Epub 2018 Apr 4.
A new family of melatonin receptor ligands, characterized by a tetrahydroquinoline (THQ) scaffold carrying an amide chain in position 3, was devised as conformationally constrained analogs of flexible N-anilinoethylamides previously developed. Molecular superposition models allowed to identify the patterns of substitution conferring high receptor binding affinity and to support the THQ ring as a suitable scaffold for the preparation of melatonin ligands. The biological activity of 3-acylamino-THQs was compared with that of the corresponding tetralin derivatives. The THQ ring proved to be a versatile scaffold for easy feasible MT and MT ligands, which resulted as more polar bioisosteres of their tetralin analogs. Potent partial agonists, with subnanomolar binding affinity for the MT receptor, were obtained, and a new series of THQ derivatives is presented. The putative binding mode of potent THQs and tetralines was discussed on the basis of their conformational equilibria as inferred from molecular dynamics simulations and experimental NMR data.
设计了一类新型的褪黑素受体配体，其特征为带有酰胺链的四氢喹啉（THQ）骨架，位于 3 位，作为先前开发的柔性 N-苯胺乙基酰胺的构象受限类似物。分子叠加模型允许确定赋予高受体结合亲和力的取代模式，并支持 THQ 环作为制备褪黑素配体的合适支架。3-酰氨基-THQs 的生物学活性与相应的四氢萘衍生物进行了比较。THQ 环被证明是一个通用的支架，易于制备 MT 和 MT 配体，它们是其四氢萘类似物的更极性的生物等排体。获得了具有亚纳摩尔结合亲和力的有效部分激动剂，并且提出了一系列新的 THQ 衍生物。根据从分子动力学模拟和实验 NMR 数据推断的构象平衡，讨论了有效 THQs 和四氢萘的假定结合模式。
