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

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.

Discovery of 7-Azanorbornane-Based Dual Agonists for the Delta and Kappa Opioid Receptors through an In Situ Screening Protocol

“…The triazoles selected above were synthesized by the standard click reactions using copper (II) sulfate pentahydrate and sodium L-ascorbate as the catalysts [30] (Scheme 2). Then, their agonistic activities were determined (Figure 3).…”

“…δ = 1.49-1.56 (m, 1H), 1.56-1.69 (m, 1H), 1.69-2.03 (m, 2H), 2.08-2.43 (m, 3H), 2.89 (br s, 1H × 50/100), 3.05 (br s, 1H × 50/100), 4.07 (br s, 1H), 4.78 (br s, 1H), 7.39 (d, J = 5.9 Hz, 2H), 8.71 (d, J = 5.9 Hz, 2H) ppm; 13 C NMR (CDCl 3 , 100 MHz): Splits of some peaks were observed due to the existence of rotamers. δ = 23.5 (1C × 50/100), 25.4 (1C × 50/100), 28.9 (1C × 50/100), 30…”

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

“…Interestingly, further efforts devoted to the structure optimization concerning the substituent on the N7 of the azanorbornane scaffold of the most active compound 23 led to the discovery of the putative β-arrestin-biased superagonist 25 ( Figure 9 C). 64 Since the effect of 25 was only partially blocked by a competitive antagonist, its binding to an allosteric site was also hypothesized. Moreover, this study suggests that, despite its easy-to-perform nature, the calcium assay alone might not be sufficient to completely highlight all the remarkable features of the GHS-R1a ligands.…”

“…This effect was contrasted by pretreatment with a competitive GHS-R1a antagonist, demonstrating that they bind to the orthosteric site of the receptor. Interestingly, further efforts devoted to the structure optimization concerning the substituent on the N7 of the azanorbornane scaffold of the most active compound 23 led to the discovery of the putative β-arrestin-biased superagonist 25 (Figure C) . Since the effect of 25 was only partially blocked by a competitive antagonist, its binding to an allosteric site was also hypothesized.…”

The physiological mechanism and effect of resistance exercise on cognitive function in the elderly people

“…Growth hormone (GH) is the master of all hormones, and it is also the key element for all brain and body cells to grow into adulthood. It can not only control energy allocation but also counteract the natural aging of cells ( 56 ). GH mostly exists in the hippocampus, inferior hypothalamus, putamen, and choroid plexus in the brain.…”