发现一种具有功能选择性的胃饥饿素受体（GHSR）配体，可调节大脑多巴胺。
Discovery of a functionally selective ghrelin receptor (GHSR) ligand for modulating brain dopamine.
机构信息
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.
National Center for Advancing Translational Sciences, NIH Division of Preclinical Innovation, Rockville, MD 20892.
出版信息
Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2112397119. doi: 10.1073/pnas.2112397119. Epub 2022 Mar 3.
SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR 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 conformations toward Gα activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR-related brain disorders involving the pathological dysregulation of dopamine.
意义
生长激素促分泌素受体-1a（GHSR）信号的调节是治疗代谢、衰老和成瘾等大脑疾病的一种很有前途的策略。GHSR 的激活通过不同的、药理学上可分离的 G 蛋白和β-arrestin（βarr）依赖性信号通路，产生多种生理效应。因此，通路选择性调节可以实现更好的药物治疗，在提高治疗效果的同时减轻副作用。在这里，我们描述了一种脑穿透性小分子 N8279（NCATS-SM8864）的发现，它使 GHSR 构象偏向于 Gα 激活，并减少了小鼠中异常的多巴胺能行为。N8279 代表了一种很有前途的化学支架，可以推进与 GHSR 相关的大脑疾病的更好治疗方法的发展，这些疾病涉及多巴胺的病理性失调。
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