Discovery of a functionally selective ghrelin receptor (GHSR <sub>1a</sub> ) ligand for modulating brain dopamine
Joshua Gross, D. W. Kim, Yang Zhou, Daniel J. Jansen, Lauren M. Slosky, Nicholas Clark, Caroline Ray, Xin Hu, Noel Southall, Anyang Wang, Xin Xu, Elena Barnaeva, William C. Wetsel, Marc Ferrer, Juan Marugán, Marc G. Caron, Lawrence S Barak, Krisztián Tóth
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.