Identification of a Putative β‐Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR)

Ghrelin is a pleiotropic feeding hormone which also has a pivotal role in the central nervous system. Upon the activation of its receptor, growth hormone secretagogue receptor (GHSR), the Gα q/11 -mediated and the β-arrestin-mediated signaling pathways are activated. As the β-arrestin pathway is a potential drug target, there is a strong need for β-arrestin-biased GHSR modulators. Activation of the β-arrestin pathway should inhibit the Gα q/11 -mediated calcium flux through the internalization of the receptor. Hence, we used the antagonistic activity in the calcium assay as the first screening for the β-arrestin activation. By conducting the second screening assay for the β-arrestin activation based on extracellular signal regulated kinase (ERK) 1/2 phosphorylation, we discovered a putative β-arrestin-biased superagonist. The activity of the compound was not completely blocked with the competitive antagonist, which implies that the effect is mediated, at least partly, by allosteric binding of the compound.