Identification of an Antagonist Targeting G Protein and β-Arrestin Signaling Pathways of 5-HT₇R

Abstract

In consideration of the limited number of FDAapproved drugs for autism spectrum disorder (ASD), significant efforts have been devoted to identifying novel drug candidates. Among these, 5-HT 7 R 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 3 and biphenyl-3-yl-dihydroimidazoles 4 as 5-HT 7 R modulators. Through extensive biological tests of 3 and 4 in G protein and β-arrestin signaling pathways of 5-HT 7 R, it was determined that 2-(2′-methoxy-[1,1′-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole 4h acted as a 5-HT 7 R antagonist in both signaling pathways. In in vivo study with Shank3 −/− transgenic (TG) mice, the self-grooming behavior test was performed with 4h, resulting in a significant reduction in the duration of self-grooming. In addition, an immunohistochemical experiment with 4h 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.