Structure-Activity Optimization of N-Arylindole GPR52 Agonists for Enhanced Antipsychotic Efficacy: Design, Synthesis, and Pharmacological Evaluation

Abstract

GPR52 is a promising therapeutic target for schizophrenia, capable of addressing positive, negative, and cognitive symptoms simultaneously. In this study, we designed and synthesized a series of N-arylindole GPR52 agonists by optimizing the "m6" linker configuration, hydrophilic head groups, and hydrophobic tails. Among them, three compounds (H11, H20, H26) exhibited good GPR52 potency and inhibition rates in the MK-801-induced hyperlocomotion model, with ED50 values of 6.18-6.92 mg/kg. Structure-activity relationship studies revealed that balanced flexibility and hydroxyl group incorporation were critical for activity. Molecular docking confirmed stable binding interactions with GPR52's "bird's claw" pocket, while ADMET predictions supported favorable drug-like properties. These designed small molecules will facilitate the development of novel GPR52 agonists.