Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivative as pontential antipsychotics

López Muñoz, Laura; Aranda, Reyes; Villalba, Karen; Raviña, Enrique; Masaguer, Christian F.; Brea, José; Areias, Filipe; Domínguez, Eduardo; Selent, Jana; Sanz, Ferran; Loza, María I.; Pastor Maeso, Manuel

doi:http://dx.doi.org/10.1021/jm800602w

Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivative as pontential antipsychotics

Citation

Aranda R, Villalba K, Raviña E, Masaguer CF, Brea J, Areias F et al. Synthesis, Binding Affinity, and Molecular Docking Analysis of New Benzofuranone Derivatives as Potential Antipsychotics. J Med Chem. 2008;51(19):6085-94. DOI: 10.1021/jm800602w

Abstract

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitarget/nstrategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in an/neffort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Through/nbiological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residues/nS3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity between/nthese new compounds for this group of receptors. Specifically, the ability of these compounds to establish/none or two H-bonds with these key residues appears to explain their difference in affinity. In addition, we/ndescribe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychotic/neffects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinities/nfor D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.