Open AccessDiscovery of a functionally selective ghrelin receptor (GHSR 1a ) ligand for modulating brain dopamine
Author(s) -
Joshua Gross,
D. W. Kim,
Yang Zhou,
Daniel J. Jansen,
Lauren M. Slosky,
Nicholas Clark,
Caroline Ray,
Xin Hu,
Noel Southall,
A. Wang,
Xin Xu,
Elena Barnaeva,
Wetsel Wc,
Marc Ferrer,
Juan Marugán,
Marc G. Caron,
Lawrence S Barak,
K. Tóth
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2112397119
Subject(s) - ghrelin , dopaminergic , dopamine , signal transduction , receptor , growth hormone secretagogue receptor , dopamine receptor , neuroscience , addiction , microbiology and biotechnology , g protein coupled receptor , endocrinology , medicine , chemistry , biology , biochemistry
Significance The 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.