Discovery of G Protein-Biased Antagonists against 5-HT7R

Introduction

G protein-coupled receptors (GPCRs) mediate many physiological signals through G proteins and through β-arrestin–dependent pathways; ligands that preferentially activate one pathway over the other (biased ligands) can yield therapeutic benefits and fewer side effects. Among serotonin receptors, the 5-HT7 receptor (5-HT7R) is a Gs-coupled GPCR that elevates intracellular cAMP, is highly expressed in the central nervous system, and has been implicated in thermoregulation, circadian rhythm, cognition and neurodevelopmental disorders including autism spectrum disorders (ASD). Previous work identified β-arrestin–biased and conventional agonists/antagonists for 5-HT7R, but, according to the extracted text, a ligand with preferential activation of the Gs protein pathway had not been reported. Lee and colleagues set out to design, synthesise and pharmacologically evaluate a series of 6-chloro-2′-methoxy biphenyl derivatives bearing different amine moieties to identify Gs protein–biased ligands at 5-HT7R. The study combined medicinal chemistry, in vitro binding and functional assays (Gs-mediated cAMP production and β-arrestin recruitment), selectivity profiling across serotonin receptor subtypes, in vitro ADME (CYP inhibition and microsomal stability), in vivo pharmacokinetics in mice, and a behavioural test (self-grooming) in Shank3 transgenic mice to probe a potential link between 5-HT7R signalling bias and ASD-relevant stereotyped behaviour.