SELECTIVE ACTIONS OF MGLU5 RECEPTOR NEGATIVE ALLOSTERIC MODULATORS

摘要 中枢神经系统疾病的成本和后果，如成瘾、自闭症、焦虑和 抑郁症给美国社会带来了巨大的负担。尽管取得了重大进展， 对这些疾病的治疗是有限的，而且有许多副作用。因此更安全、更具体 药物将具有很高的临床实用价值。一个高水平的可药物靶点是代谢性 谷氨酸受体，mGlu5，在所有这些疾病中发挥关键作用。事实上，有几个 MGlu5负变构调节剂(NAMS)目前正处于不同程度的临床试验中 效率的问题。除了化学支架外，药物的疗效还取决于细胞特性 以及受体的位置。因为我们之前的工作表明，60%-90%的mGlu5位于 在连接到不同信号系统的胞内膜上，mGlu5的位置可能 在它的调节能力中起着关键的作用。事实上，我们的新数据显示，细胞内 受体是建立海马和纹状体LTD所必需的，并足以阻断 慢性疼痛行为。然而，警告是存在的，因为这些最初的对手中的许多人已经- 靶向效应、可变药效和快速清除。为了克服这些问题，我们有 从Eli Lilly，Inc.获得了五个新的高度选择性mGlu5 NAM。我们的初始数据包括在 应用表明，这些NAM中至少有一个只能阻断细胞表面的mGlu5，而 其他的则是自由渗透的。使用药理学、分子和遗传工具以及我们的 渗透性和非渗透性激动剂和拮抗剂的独特组合，在此我们建议 为了测试这些新的NAM是否阻断纹状体细胞表面或细胞内的mGlu5以及 海马体，与许多中枢神经系统疾病相关的区域。差别化监管的NAMS MGlu5将在突触可塑性的体外模型中进一步测试。作为突触后mGlu5 海马区和纹状体内源性大麻素介导的LTD需要激活 拟议的研究还将确定哪个受体池参与突触前 内源性大麻素有限公司像这里测试的NAMS这样的新监管机构将1)推动这一概念 受体调节的细胞背景可能改变其有效性；2)决定 细胞内mGlu5是突触活动的基本方面；3)提供关键的 S)为未来在活体中枢神经系统的应用提供了工具。在治疗层面上， 功能性细胞内受体为选择性地定制激动剂和/或 任何一种受体的拮抗剂。未来针对细胞表面药物的研究与 细胞内受体可能会带来治疗成瘾、自闭症、焦虑症和 其他mGlu5调节性疾病。

ABSTRACT The cost and consequences of CNS disorders such as addiction, autism, anxiety, and depression place an enormous burden on American society. Despite significant progress, treatments for these disorders are limited and have many side effects. Thus safer, more specific drugs would have high clinical utility. One high level drug-able target is the metabotropic glutamate receptor, mGlu5, which plays a critical role in all of these disorders. Indeed, several mGlu5 negative allosteric modulators (NAMs) are currently in clinical trials with varying degrees of efficacy. Besides the chemical scaffold, drug efficacy is also determined by cellular properties and receptor location. Because our previous work has shown that 60-90% of mGlu5 is located on intracellular membranes where it couples to distinct signaling systems, mGlu5 location may play a key role in its ability to be modulated. In fact our new data show that the intracellular receptor is necessary for establishing hippocampal and striatal LTD and sufficient in blocking chronic pain behaviors. Caveats exist, though, since many of these initial antagonists have off- target effects, variable efficacy, and rapid clearance. To overcome these issues we have obtained five new highly selective mGlu5 NAMs from Eli Lilly, Inc. Our initial data included in this application indicate that at least one of these NAMs only blocks cell surface mGlu5 whereas others are freely permeable. Using pharmacological, molecular and genetic tools as well our unique combination of permeable and impermeable agonists and antagonists, here we propose to test whether these novel NAMs block cell surface or intracellular mGlu5 in the striatum and the hippocampus, regions relevant to many CNS disorders. NAMs that differentially regulate mGlu5 will be further tested in ex vivo models of synaptic plasticity. As postsynaptic mGlu5 activation is required for hippocampal and striatal endocannabinoid-mediated LTD, the proposed studies will also determine which receptor pool contributes to presynaptic endocannabinoid-LTD. New regulators like the NAMs tested here will 1) further the concept that the cellular context of receptor modulation may alter its efficacy; 2) determine whether intracellular mGlu5 underlies fundamental aspects of synaptic activity; and 3) provide a critical tool (s) for future in vivo CNS applications. At the therapeutic level, the occurrence of a functional intracellular receptor opens the door to selectively tailoring agonists and/or antagonists to either receptor pool. Future studies targeting drugs to cell surface versus intracellular receptors might lead to new therapeutic tools for addiction, autism, anxiety, and other mGlu5-modulated disorders.