Patnaik Samarjit, Marugan Juan, Liu Ke, Zheng Wei, Thorsell Annika, Eskay Robert, Southall Noel, Heilig Markus, Inglese James, Austin Christopher
NIH Chemical Genomics Center, 9800 Medical Center Dr, Building B, Bethesda, MD, 20892-3370
National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892
The neuropeptide S receptor (NPSR) is a G-protein coupled receptor, first described by Sato and co-workers in 2004. Further research has detailed the distribution and expression of neuropeptide S (NPS) precursor mRNA and NPSR mRNA in various regions of the brain. Central administration of NPS has been shown to promote hyperlocomotion and wakefulness in various rodent models, implicating the importance of this circuitry in the control of sleep, stress, anxiety and arousal. Also, two polymorphisms of NPSR have been linked to asthma. Recent findings suggest that the receptor might be coupled to signaling through the Gq, Gs and mitogen-activated protein kinase (MAPK) pathways. Although several potent inhibitors on the NPS/NPSR signaling pathway have been found, none of these compounds have as yet demonstrated robust in vivo efficacy in multiple animal models. Thus, there is a clear need to discover novel small molecule antagonists of the NPSR to help probe NPS/NPSR pharmacology, and to validate the importance of this neurocircuitry in animal models. The present report discloses the discovery and characterization of a potent NPSR antagonist having an imidazo-pyridinium molecular core and an unusual, yet stable phosphorothioyl species. The small molecular probe ML154 (CID-46930969) is the most potent in vivo active compound yet reported, and has promising microsomal stability compared to other lead NPSR antagonists disclosed in the literature. The probe completely antagonizes NPS activation of the NPS/NPSR neurocircuitry in a food intake rat model using intracerebroventricular (icv) administration. This potent probe molecule can be used as a tool molecule by biologists interested in understanding NPS/NPSR pharmacology and the role of NPSR antagonism in sleep, anxiety, food intake, and addiction.
神经肽S受体（NPSR）是一种G蛋白偶联受体，于2004年由佐藤及其同事首次描述。进一步的研究详细阐述了神经肽S（NPS）前体mRNA和NPSR mRNA在大脑各个区域的分布和表达。在各种啮齿动物模型中，已证明中枢给予NPS可促进活动亢进和觉醒，这表明该神经回路在睡眠、应激、焦虑和觉醒控制中的重要性。此外，NPSR的两种多态性与哮喘有关。最近的研究结果表明，该受体可能通过Gq、Gs和丝裂原活化蛋白激酶（MAPK）途径与信号传导偶联。尽管已发现几种对NPS/NPSR信号通路有效的抑制剂，但这些化合物在多种动物模型中均未显示出强大的体内疗效。因此，显然需要发现新型的NPSR小分子拮抗剂，以帮助探究NPS/NPSR药理学，并验证该神经回路在动物模型中的重要性。本报告披露了一种具有咪唑并吡啶鎓分子核心和一种不寻常但稳定的硫代磷酰基的强效NPSR拮抗剂的发现和特性。小分子探针ML154（CID-46930969）是迄今报道的体内活性最强的化合物，与文献中披露的其他NPSR先导拮抗剂相比，具有良好的微粒体稳定性。在食物摄入大鼠模型中，通过脑室内（icv）给药，该探针完全拮抗NPS对NPS/NPSR神经回路的激活作用。这种强效探针分子可被对理解NPS/NPSR药理学以及NPSR拮抗作用在睡眠、焦虑、食物摄入和成瘾中的作用感兴趣的生物学家用作工具分子。
