Discovery of a functionally selective ghrelin receptor (GHSR 1a ) ligand for modulating brain dopamine

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.