Discovery of a functionally selective ghrelin receptor (GHSR<sub>1a</sub>) ligand for modulating brain dopamine.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35239443.
- Also identified by DOI 10.1073/pnas.2112397119 and PMC identifier 8915830.
- Licence recorded as CC BY-NC-ND.
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Abstract
SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR<sub>1a</sub>) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR<sub>1a</sub> 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<sub>1a</sub> conformations toward Gα<sub>q</sub> activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR<sub>1a</sub>-related brain disorders involving the pathological dysregulation of dopamine.
Medical subject headings
- Brain
- Dopamine
- GTP-Binding Protein alpha Subunits, Gq-G11
- Receptors, Ghrelin