Identification of an Antagonist Targeting G Protein and ß-Arrestin Signaling Pathways of 5-HT7R.
ACS Chem Neurosci
; 15(5): 1026-1041, 2024 03 06.
Article
em En
| MEDLINE
| ID: mdl-38387042
ABSTRACT
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-HT7R 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-HT7R modulators. Through extensive biological tests of 3 and 4 in G protein and ß-arrestin signaling pathways of 5-HT7R, it was determined that 2-(2'-methoxy-[1,1'-biphenyl]-3-yl)-4,5-dihydro-1H-imidazole 4h acted as a 5-HT7R 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.
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Base de dados:
MEDLINE
Assunto principal:
Compostos de Bifenilo
/
Transtorno do Espectro Autista
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article