Discovery of a functionally selective ghrelin receptor (GHSR _1a ) ligand for modulating brain dopamine

Abstract

Significance The modulation of growth hormone secretagogue receptor-1a (GHSR 1a ) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR 1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein– and β-arrestin (βarr)–dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR 1a conformations toward Gα q activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR 1a -related brain disorders involving the pathological dysregulation of dopamine.

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

“…According to their findings, ligands that establish simultaneous interactions with residues in TM5 and TM6 seem to have an unbiased coupling profile, whereas exclusive interaction with TM5 promotes G protein bias, in particular G oB . Note also that contacts with extracellular receptor regions (e.g., ECL2) drive signaling (un)bias, as reported for the Ghrelin receptor [ 21 ] or the adenosine 1A receptor [ 22 ]. Interestingly, in a later study, the authors propose that the same allosteric fragment (VCP171) binds to different allosteric sites in the ECL2 of the adenosine 1A receptor, which triggers different signaling responses.…”