N‐(Biphenyl‐3‐ylmethyl)ethanamines as G protein‐biased agonists of 5‐HT7R

Abstract

AbstractThere has been much attention to biased ligands of G protein‐coupled receptors (GPCRs) for potential pharmacological benefits. Recently, we reported N‐((6‐chloro‐2'‐methoxy‐[1,1'‐biphenyl]‐3‐yl)methyl)ethanamine 1 as G protein‐biased agonist of 5‐HT7R, which could be used as a chemical probe for the study on treatment discovery of autism spectrum disorder. Herein, we describe the synthesis of derivatives of the compound 1 and their biological evaluations in both G protein and β‐arrestin signaling pathway. Total 16 compounds were synthesized and evaluated, and the compounds 3c, 3f, 3i, and 3p could be called as G protein‐biased agonists like the compound 1. Among the four compounds, the compound 3c was the best in efficacy with an Emax value of 73% and the compound 3f was the most potent agonist with an EC50 value of 0.094 μM.