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

2022; National Academy of Sciences; Volume: 119; Issue: 10 Linguagem: Inglês

10.1073/pnas.2112397119

1091-6490

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,

Adipose Tissue and Metabolism

SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a 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 GHSR1a conformations toward Gαq activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR1a-related brain disorders involving the pathological dysregulation of dopamine.