Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivatives as potential Antipsychotics

被引:31
|
作者
Aranda, Reyes [1 ]
Villalba, Karen [1 ]
Ravina, Enrique [1 ]
Masaguer, Christian F. [1 ]
Brea, Jose [2 ]
Areias, Filipe [2 ]
Dominguez, Eduardo [2 ]
Selent, Jana [3 ]
Lopez, Laura [3 ]
Sanz, Ferran [3 ]
Pastor, Manuel [3 ]
Loza, Maria I. [2 ]
机构
[1] Univ Santiago de Compostela, Dept Quim Organ, Quim Farmaceut Lab, E-15782 Santiago De Compostela, Spain
[2] Univ Santiago de Compostela, Dept Farmacol, Fac Farm, E-15782 Santiago De Compostela, Spain
[3] Univ Pompeu Fabra, Res Unit Biomed Informat, GRIB, IMIM, E-08003 Barcelona, Spain
关键词
D O I
10.1021/jm800602w
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitarget strategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in an effort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Through biological and computational studies of 5-HT2A and D-2 receptors, we identified the receptor serine residues S3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity between these new compounds for this group of receptors. Specifically, the ability of these compounds to establish one or two H-bonds with these key residues appears to explain their difference in affinity. In addition, we describe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychotic effects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinities for D-2 and 5-HT2A receptors, and a 5-HT2A/D-2 ratio was predictive of an atypical antipsychotic profile.
引用
收藏
页码:6085 / 6094
页数:10
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