Synthesis of 2-(3-aminopropyl)benzopyrans as potential antipsychotic agents targeting D2/D3 and 5-HT2A receptors

Fecha de publicación: 01/11/2025 Fecha Ahead of Print: 01/07/2025

Autores de INCLIVA

Alvaro Bernabeu Sanchís

Autor
Ainhoa Natividad García Martín

Autor
Laura Vila Dasí

Autor
Diego Cortes Martinez

Autor
Nuria Cabedo Escrig

Autor

Participantes ajenos a INCLIVA

Varela MJ
Villarroel-Vicente C
Loza MI
Brea J

Grupos y Plataformas de I+D+i

Grupo de investigación en Química Médica para el Desarrollo de Fármacos

Responsable de Plataforma

Nuria Cabedo Escrig
Unidad de Cromatografía Líquida Analítica

Responsable de Plataforma

Nuria Cabedo Escrig

Abstract

The high prevalence and complexity of neurological and psychiatric disorders, such as schizophrenia, makes the development of new, safer and more effective neuroleptic drugs a continuing need. We have synthesized 2-(3-aminopropyl)benzopyrans bearing a chroman-6-ol nucleus, a 3-carbon atoms side chain, and an ionisable nitrogen into different amine frameworks. The specific affinity of 2-(3-aminopropyl)benzopyrans was determined by competition binding assays of radioligands on membranes from CHO cells stably expressing the cloned human D2, D3 and 5-HT2A receptors. Results showed that benzopyrans 9b, 9e, 9f and 11, all of them with a free phenol group in the chromanol nucleus, displaced the specific radioligand for hD2 and hD3 in the submicromolar or low micromolar range. Molecular docking analysis shows that the nitrogen atom of amine substituents plays a key role to bind the orthosteric binding site of both D2R and 5-HT2AR, as well as the oxygen atom of phenol group for binding to the D2R. In addition, functional assays revealed a partial hD2 agonism and h5-HT2A antagonism for 9b, 9e and 11 derivatives as new atypical antipsychotic agents, while compound 9f behaved as a D2 antagonist like a first-generation neuroleptic.