Functional effects of mGluR potentiators in the CNS

mGluR 增强剂在中枢神经系统中的功能作用

基本信息

批准号：
7914849
负责人：
P Jeffrey Conn
金额：
$ 7.75万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Animal and clinical studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) could provide a novel approach for the treatment of anxiety disorders and schizophrenia. However, group II mGlu receptor agonists activate both mGlu2 and mGlu3, and the relative contributions of these two receptor subtypes to the actions of these drugs are not known. Thus, there is a critical need to determine whether activation of a specific group II mGlu receptor subtype (mGlu2 or mGlu3) could elicit the behavioral and electrophysiological effects of group II mGlu receptor agonists that are relevant to their potential therapeutic efficacy. Furthermore, development of tolerance and adverse effects of direct agonists could limit their clinical use. Thus, it will be important to develop novel approaches to increasing activity of these receptors that may have advantages relative to direct agonists. In recent months, a novel class of compounds has been discovered that act as selective allosteric potentiators of the mGlu2 receptor subtype. These compounds do not activate mGlu2 directly but act at an allosteric site to potentiate glutamate-induced activation of the receptor. These compounds represent the first clear departure from glutamate analogs as mGlu2 activators are the first compounds that are highly selective for mGlu2 relative to mGlu3 or other mGlu receptor subtypes. However, the functional effects of these compounds in systems relevant to the therapeutic efficacy of group II mGlu receptor agonists have not been determined. We propose a series of studies in which we will determine the effects of allosteric potentiators of mGlu2 on electrophysiological responses to group II mGlu receptor activation in cell populations that have been postulated to be important for the therapeutic effects of these compounds. In addition, we will systematically evaluate the behavioral effects of allosteric mGlu2 potentiators in animal models predictive of anxiolytic and antipsychotic activity. Finally, we will determine whether direct agonists and allosteric potentiators differ in their propensity to induce desensitization and behavioral tolerance after chronic administration. These studies will build on the exciting advances suggesting a potential therapeutic utility of group II mGlu receptor activators and could provide a novel approach to increasing activity of these receptors that for development of new therapeutic agents.

描述（由申请人提供）：动物和临床研究表明，II组代谢剂谷氨酸（MGLU）受体（MGLU2和MGLU3）的激动剂可以为治疗焦虑症和精神分裂症的治疗提供一种新颖的方法。然而，II组MGLU受体激动剂都激活了MGLU2和MGLU3，这两个受体亚型对这些药物的作用的相对贡献尚不清楚。因此，迫切需要确定特定组II组MGLU受体亚型（MGLU2或MGLU3）是否可以引起与潜在的治疗功效相关的II组MGLU受体激动剂的行为和电生理效应。此外，直接激动剂的耐受性和不利影响的发展可能会限制其临床使用。因此，开发新的方法来增加这些受体的活性，而这些受体的活性相对于直接激动剂而言可能具有优势。近几个月来，已经发现了一类新型化合物作为MGLU2受体亚型的选择性变构型增强剂。这些化合物不会直接激活MGLU2，而是在变构的位点起作用，以增强谷氨酸诱导的受体激活。这些化合物代表了与谷氨酸类似物的第一个明确偏离，因为MGLU2激活剂是相对于MGLU3或其他MGLU受体亚型的首批化合物。但是，尚未确定这些化合物在与II组MGLU受体激动剂的治疗功效相关的系统中的功能效应。我们提出了一系列研究，其中我们将确定MGLU2的变构增强剂对细胞群体II组MGLU受体激活的电生理反应的影响，这些反应对这些化合物的治疗作用很重要。此外，我们将系统地评估变构MGLU2增强剂在动物模型中预测抗焦虑和抗精神病药活性的行为效应。最后，我们将确定直接的激动剂和变构增强剂在长期给药后引起脱敏和行为耐受性的倾向是否有所不同。这些研究将基于令人兴奋的进步，这表明II组MGLU受体激活剂具有潜在的治疗效用，并可以提供一种新型的方法来增加这些受体的活性，以开发新的治疗剂。