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

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-HT_2A 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-HT_2AR, 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-HT_2A 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.