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， 萧条给美国社会带来了巨大负担。尽管取得了重大进展， 对这些疾病的治疗是有限的并且具有许多副作用。因此更安全，更具体 药物将具有很高的临床效用。一个高水平的药物靶点是代谢型 谷氨酸受体，mGlu 5，它在所有这些疾病中起着关键作用。事实上， mGlu 5负变构调节剂（NAM）目前处于不同程度的临床试验中， 的功效。除了化学支架外，药物功效还取决于细胞特性 和受体位置。因为我们之前的研究表明，60-90%的mGlu 5位于 在细胞内膜上，它与不同的信号系统偶联，mGlu 5的位置可能 在其调节能力中起着关键作用。事实上，我们的新数据表明， 受体是建立海马和纹状体LTD所必需的，并足以阻断 慢性疼痛行为不过，也有警告，因为这些最初的对手中有许多已经关闭- 靶向效应、可变功效和快速清除。为了解决这些问题，我们 从Eli Lilly，Inc.获得五种新的高选择性mGlu 5 NAM。我们的初步数据包括在这 应用表明，这些NAM中的至少一种仅阻断细胞表面mGlu 5，而 其它的是自由渗透的。利用药理学、分子学和遗传学工具， 独特的渗透性和非渗透性激动剂和拮抗剂的组合，在这里，我们建议 为了测试这些新的NAM是否阻断纹状体中的细胞表面或细胞内mGlu 5， 海马，与许多中枢神经系统疾病相关的区域。差异调节的NAM 将在突触可塑性的离体模型中进一步测试mGlu 5。作为突触后mGlu 5 海马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些受体池有助于突触前 内源性大麻素有限公司。新的监管机构，如NAMs测试这里将1）进一步的概念 受体调节的细胞环境可能改变其功效; 2）确定是否 细胞内mGlu 5是突触活动的基本方面的基础;和3）提供关键的 用于未来体内CNS应用的工具。在治疗水平上， 功能性细胞内受体打开了选择性定制激动剂和/或 受体池的拮抗剂。靶向细胞表面的药物与 细胞内受体可能会导致成瘾，自闭症，焦虑， 其他mGlu 5调节的疾病。

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.