title: Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivatives as potential antipsychotics.
abstract: 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 D2 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 D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.
authors.affiliation: Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Reyes
authors.initials: R
authors.lastname: Aranda
authors.forename: Karen
authors.initials: K
authors.lastname: Villalba
authors.forename: Enrique
authors.initials: E
authors.lastname: Raviña
authors.forename: Christian F
authors.initials: CF
authors.lastname: Masaguer
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: Filipe
authors.initials: F
authors.lastname: Areias
authors.forename: Eduardo
authors.initials: E
authors.lastname: Domínguez
authors.forename: Jana
authors.initials: J
authors.lastname: Selent
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.forename: María I
authors.initials: MI
authors.lastname: Loza
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D003001:Cloning, Molecular; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects; D016415:Sequence Alignment / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001572:Benzofurans; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2