Discovery of a functionally selective ghrelin receptor (GHSR_1a) ligand for modulating brain dopamine.

ABSTRACT: SignificanceThe 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

SUBMITTER: Gross JD 

PROVIDER: S-EPMC8915830 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature