Identification of a Putative β‐Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR). (1st August 2021)

• Record Type: Journal Article
• Authors: Karaki, Fumika; Oki, Tomoya; Sakao, Yuma; Sato, Noriko; Hirayama, Shigeto; Miyano, Kanako; Uezono, Yasuhito; Fujii, Hideaki
• Is Part Of: ChemMedChem. Volume 16:Number 22(2021)
• Page Start: 3463
• Page End: 3476
• Publication Date: 2021-08-01
• Subjects: β-arrestin-biased agonist -- ghrelin -- growth hormone secretagogue receptor (GHSR) -- medicinal chemistry -- receptors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100322
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 Gαq/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 Gαq/11 ‐mediated calcium flux through 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. Abstract : Orexigenic effect modulation : The growth hormone secretagogue receptor (GHSR) is the receptor for the peptide hormone ghrelin. The β‐arrestin pathway of this receptor is recognized as a potential drug target, and hence there is a strong need for modulators of this pathway. In this study we discovered a putative β‐arrestin‐biased superagonist by performing calcium assays in which the activation of the β‐arrestin pathways should inhibit G protein‐mediated calcium flux.