Identification of an Antagonist Targeting G Protein and β-Arrestin Signaling Pathways of 5-HTR.

In consideration of the limited number of FDA-approved drugs for autism spectrum disorder (ASD), significant efforts have been devoted to identifying novel drug candidates. Among these, 5-HTR modulators have garnered considerable attention due to their potential in alleviating autism-like behaviors in ASD animal models. In this study, we designed and synthesized biphenyl-3-ylmethylpyrrolidines and biphenyl-3-yl-dihydroimidazoles as 5-HTR modulators. Through extensive biological tests of and in G protein and β-arrestin signaling pathways of 5-HTR, it was determined that 2-(2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1-imidazole acted as a 5-HTR antagonist in both signaling pathways. In study with Shank3 transgenic (TG) mice, the self-grooming behavior test was performed with , resulting in a significant reduction in the duration of self-grooming. In addition, an immunohistochemical experiment with restored reduced neurogenesis in Shank3 TG mice, which is confirmed by the quantification of doublecortin (DCX) positive neurons, suggesting the promising therapeutic potential of 4h.