Partial Antagonists of mGluR5 for Treatment of Cocaine Addiction

描述（由申请人提供）：代谢性谷氨酸受体（mGluR） mGluR5亚型在调节药物滥用的奖励效应中起关键作用，最近的研究表明，选择性mGluR5拮抗剂可能为治疗成瘾障碍提供令人兴奋的新方法。我们已经确定了多种新的mGluR5拮抗剂，包括多种独特的支架以及基于现有支架的具有新活性的化合物。最值得注意的是，我们发现了一类新的化合物作为mGluR5的高选择性部分拮抗剂。不像部分激动剂，已确定为其他受体，这些化合物不会激活受体到任何水平。然而，它们部分阻断了谷氨酸对受体的激活，而没有完全阻断受体的激活。我们现在有多种部分拮抗剂，当受体上的变构结合位点被完全占据时，它们可以阻断mGluR5，其活性范围从10%到90%不等。这一令人兴奋的突破是传统的竞争性正构位点拮抗剂不可能实现的，但可以通过靶向变构拮抗剂位点来实现。通过采用高通量药物化学技术，我们将优化这些筛选导致化合物适合概念验证研究。这些新化合物将为我们的实验室提供一个前所未有的机会，以确定部分阻断mGluR5是否会对动物模型产生影响，从而预测治疗可卡因滥用的疗效，或者是否需要完全阻断受体。此外，这些药物将使我们能够直接评估具有不同mGluR5阻断水平的mGluR5拮抗剂的不良反应。此外，我们对部分拮抗剂活性的新理解将使我们能够优化属于现有部分拮抗剂支架的化合物以及新的化学类别，以确定用作研究工具和药物先导的最佳特性。这项研究与NIDA的使命直接相关，并有可能直接影响人类健康。我们这个项目的目标是开发一种局部mGluR5拮抗剂，具有可接受的临床前和最终临床开发特征，可能成为治疗成瘾障碍的新药。

DESCRIPTION (provided by applicant): The metabotropic glutamate receptor (mGluR) mGluR5 subtype plays a critical role in regulating the rewarding effects of drugs of abuse and recent studies suggest that selective mGluR5 antagonists may provide an exciting new approach for treatment of addictive disorders. We have identified multiple new mGluR5 antagonists, including multiple unique scaffolds as well as compounds based on existing scaffolds that have novel activities. Most notably, we discovered a novel class of compounds that act as highly selective partial antagonists of mGluR5. Unlike partial agonists that have been identified for other receptors, these compounds do not activate the receptor to any level. However, they partially block activation of the receptor by glutamate without fully blocking receptor activation. We now have multiple partial antagonists that block mGluR5 with a range of activities from 10% to 90% inhibition when the allosteric binding site on the receptor is fully occupied. This exciting breakthrough would not be possible with traditional competitive orthosteric site antagonists but is achieved by targeting the allosteric antagonist site. By employing high throughput medicinal chemistry techniques we will optimize these screening leads into compounds suitable for proof of concept studies. These novel compounds will provide an unprecedented opportunity for our labs to determine whether partial blockade of mGluR5 will have effects in animal models that predict efficacy in treatment of cocaine abuse or whether complete blockade of the receptor is required. Also, these agents will allow us to directly evaluate the adverse effects of mGluR5 antagonists that possess different levels of mGluR5 blockade. In addition, our new understanding of partial antagonist activity will allow us to optimize compounds belonging to existing partial antagonist scaffolds as well as novel chemical classes to identify optimal properties to be used as research tools and drug leads. This research has direct relevance to the mission of NIDA and has the potential to impact human health directly. Our goal for this project is to develop a partial mGluR5 antagonist with an acceptable profile for preclinical and ultimately clinical development that may become a new drug to treat addictive disorders.