A new serotonin 2A receptor antagonist with potential benefits in Non-Alcoholic Fatty Liver Disease

Abstract

Peripheral 5-hydroxytryptamine 2A receptor (5-HT2AR) could be a new pharmacological target for NASH, an evolution of NAFLD characterized by hepatic steatosis, cytoskeletal alterations, and hepatic inflammation that can arise with or without fibrosis. SJT4a is a synthetic β-carboline antagonist for 5-HT2AR developed by SJT molecular research to treat NASH. We performed a combined in silico/in vivo study on this potential drug to elucidate its activity and possible mechanism of action.The in silico protocol compares SJT4a with four known 5-HT2AR ligands with different activities (LSD, methiothepin, zotepine, risperidone). We performed molecular docking calculations, evaluation of binding energy by AI-based methods and Molecular Dynamics simulations of the five ligand-target complexes. Moreover, we used a pseudo-semantic analysis to evaluate the potential mechanism of action of SJT4a. In silico predictions and pseudo-semantic analysis suggested antagonistic activity for SJT4a. The in silico prediction was confirmed by [3H]-5HT radioligand binding together with SJT4a competition analysis in CHO-K1 cell cultures expressing 5-HT2AR.SJT4a was then tested in vivo. We investigated the effect of 8 weeks of treatment with SJT4A on metabolic parameters, liver pathology, NAFLD activity score, and fibrosis stage in male DIO-NASH C57BL/6 J mice diet-induced obesity fed with an obesogenic diet compared with DIO-NASH and LEAN-CHOW vehicles. In our tests, SJT4a showed intense activity in diminishing the most relevant hallmarks of NASH in the DIO-NASH mice model. We proposed a possible mode of action for SJT4a based on its 5-HT2AR antagonist activity.