Discovery of G Protein-Biased Antagonists against 5-HT7R

This study explored the effects of a number of synthetic psychoactive drugs, such as the 2C-family, on the serotonin receptor 5-HT7R. The ability of a particular 2C compound to bind 5-HT7R over other subtypes and reduce self-grooming time in mice suggests that 5-HT7R could be a potential target for treating autism.


“5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3, which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and β-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3–/– transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.”

Authors: Rina Kwang, Jieon Lee, Doyoung Kim, Haeun Lee, Miyoung Yeom, Jiwan Woo, Yakdol Cho, Hak Joong Kim, Jeongjin Kim, Gyochang Keum, Byungsun Jeon & Hyunah Choo

Summary of Discovery of G Protein-Biased Antagonists against 5-HT7R


The reaction of 2-methoxyphenylboronic acid with Pd(PPh3)4,Na2CO3, DMF, reflux, and 6095% is described. The reaction also involves Boc2O, NaHCO3,H2O, THF, rt, and 77%, and HCOOH, HCOH, reflux, and 70%.

AUClast, time-averaged total body clearance, MRT, mean residence time, Vdss, apparent volume of distribution at steady state, BA, standard deviations.

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Study details

Compounds studied

Topics studied
Neuroscience Autism

Study characteristics
Animal Study

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