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

Autor:	Gross JD; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Kim DW; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Zhou Y; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Jansen D; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Slosky LM; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Clark NB; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Ray CR; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Hu X; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Southall N; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Wang A; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Xu X; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Barnaeva E; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Wetsel WC; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710.; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710., Ferrer M; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Marugan JJ; National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892., Caron MG; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Barak LS; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710., Toth K; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Mar 08; Vol. 119 (10), pp. e2112397119. Date of Electronic Publication: 2022 Mar 03.
DOI:	10.1073/pnas.2112397119
Abstrakt:	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 the development of better treatments for GHSR 1a -related brain disorders involving the pathological dysregulation of dopamine.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu