Development of Chemical Probes to Investigate the Role of NTSR1 in CNS Disorders

描述（由申请人提供）：神经降压素系统由于其调节多巴胺信号传导和传递的能力而作为治疗药物成瘾的潜在靶点吸引了大量关注。然而，尽管制药工业和学术界在过去30年中进行了广泛的努力，但仍然没有有效的、选择性NTSR 1非肽激动剂或增效剂，并且文献中仅描述了少数拮抗剂。从高通量筛选（HTS）的角度来看，大多数的注意力已经支付给NTSR 1受体和它的信号通过Gq蛋白偶联的信号转导通路之间的相互作用。然而，现在很清楚，NTSR 1可以耦合到多个G蛋白，甚至可能以G蛋白独立的方式发出信号。因此，本提案的总体目标是采用多重测定方法来驱动迭代药物化学程序，旨在鉴定NTSR 1的强效、选择性、细胞渗透阳性调节剂。为了避免错过潜在的有价值的化合物，我们的方法是在具有不同功能读数的多个基于细胞的测定中筛选化合物。这可以被视为撒下一张大网来捕获通过不同机制调节受体的化合物，然后让功能测定中的功效使我们能够为每种化合物创建细胞反应谱或“功能指纹”。这种体外功能指纹将是非常宝贵的未来评价化合物在体内，挑战是确定生理后果的功能选择性在NTSR 1。因此，我们的多重测定方法是对制药行业通常采用的单一[Ca 2 +]/FLIPR测定方法的巨大改进。 公共卫生相关性：神经降压素1受体（NTSR 1）在外周和中枢神经系统中表达，由于其调节多巴胺信号传导和传递的能力，作为治疗药物成瘾的潜在靶点引起了人们的广泛关注。该提案旨在开发一系列基于细胞的功能测定，以推动迭代的药物化学计划，旨在鉴定NTSR 1的强效、选择性、细胞渗透阳性调节剂。

DESCRIPTION (provided by applicant): The neurotensin system has attracted a lot of attention as a potential target to treat drug addiction due to its ability to modulate dopamine signaling and transmission. However, despite extensive effort by the pharmaceutical industry and academia over the past 30 years, there are still no potent, selective NTSR1 non- peptide agonists or potentiators and only a few antagonists described in the literature. From a high throughput screening (HTS) perspective most of the attention has been paid to interactions between the NTSR1 receptor and its signaling through the Gq protein-coupled signal transduction pathway. However, it is now clear that NTSR1 can couple to multiple G proteins and may even signal in a G-protein independent fashion. Hence, the overall goal of this proposal is to employ a multiple assay approach to drive an iterative medicinal chemistry program aimed at identifying potent, selective, cell penetrant positive modulators of NTSR1. To avoid missing potential valuable compounds our approach is to screen compounds in multiple cell-based assays with different functional readouts. This can be viewed as casting a wide net to capture compounds that modulate the receptor via different mechanisms and then letting the efficacy in the functional assays enable us to create a cellular response profile or 'functional fingerprint' for each compound. This in vitro functional fingerprint will be invaluable for future evaluation of compounds in vivo, the challenge being to identify physiological consequences of functional selectivity at NTSR1. Thus, our multiple assay approach is a vast improvement over the single [Ca2+]/FLIPR assay approach typically pursued by the pharmaceutical industry. PUBLIC HEALTH RELEVANCE: The neurotensin 1 receptor (NTSR1) is expressed peripherally and in the CNS and has attracted a lot of attention as a potential target to treat drug addiction due to its ability to modulate dopamine signaling and transmission. This proposal seeks to develop a series of cell-based functional assays to drive an iterative medicinal chemistry program aimed at identifying potent, selective, cell penetrant positive modulators of NTSR1.