| First Author | Gross JD | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 10 | Pages | e2112397119 |
| PubMed ID | 35239443 | Mgi Jnum | J:334541 |
| Mgi Id | MGI:7256283 | Doi | 10.1073/pnas.2112397119 |
| Citation | Gross JD, et al. (2022) Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine. Proc Natl Acad Sci U S A 119(10):e2112397119 |
| abstractText | 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 beta-arrestin (betaarr)-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 Galphaq 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. |
