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

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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 D 2 , D 3 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 hD 2 and hD 3 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 D 2 R and 5-HT 2A R, as well as the oxygen atom of phenol group for binding to the D 2 R. In addition, functional assays revealed a partial hD 2 agonism and h5-HT 2A antagonism for 9b , 9e and 11 derivatives as new atypical antipsychotic agents, while compound 9f behaved as a D 2 antagonist like a first-generation neuroleptic.

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