Modulators of Metabotropic Glutamate Receptor Subtype 2 for Cocaine Dependence

描述（由申请人提供）：这份题为“可卡因依赖的代谢性谷氨酸受体亚型2调节剂”的申请是对RFA-DA-07-006的回应。可卡因成瘾仍然是美国一个主要的公共卫生问题。迄今为止，尚未确定一种安全有效的治疗可卡因依赖的方法。因此，有很大的需要探索新的药物治疗可卡因依赖。我们计划采用多学科方法，包括化学、体外药理学和行为评估新化合物在可卡因依赖、戒断和恢复可卡因寻求行为的大鼠模型中的作用。反复暴露于可卡因会改变II组代谢型谷氨酸受体（mGluRs）的功能，mGluR2和mGluR3是由II组代谢型谷氨酸受体组成的。目前对mGluR2有选择性的化合物相对较少，而且这些化合物大多没有很好的脑穿透性。在这里，我们建议设计和合成新的mGluR2的正、负变构调节剂，它们在体内具有系统活性，并且具有良好的脑生物利用度（Specific Aim 1）。然后，在Specific Aim 2中，我们将在体外效价和选择性分析中表征这些阳性和阴性mGluR2变构调节剂。此外，我们将评估这些化合物在大脑中其他分子靶标上的潜在脱靶效应。将在大鼠中评估最有前途的类似物的药代动力学特征和脑渗透，以方便选择最佳化合物进行体内药理学研究。在Specific Aim 3中，我们将研究mGluR2阳性和阴性变弹性调节剂在大鼠可卡因依赖（延长静脉可卡因自我给药）、恢复（歧视性线索诱导的可卡因寻求行为恢复）和早期戒断（可卡因戒断期间颅内自我刺激阈值升高）模型中的作用。另外的实验将比较测试化合物对食物强化物引起的行为的影响，作为潜在的抗成瘾药物筛选的一个重要方面。预测mGluR2阳性调节剂仅会降低可卡因“依赖”大鼠自我给药的强化效应，并减弱线索诱导的可卡因寻求行为。相反，服用mGluR2阴性调节剂会逆转与可卡因戒断相关的情感症状。如果mGluR2阳性或阴性调节剂在其中一种或几种模型中有效，那么我们将实现mGluR2系统活性调节剂作为潜在的新型药物疗法治疗人类可卡因成瘾的概念验证。意义：本研究将设计并合成高效选择性mGluR2的新型化学实体，具有良好的脑穿透性，对可卡因依赖动物模型具有潜在的“治疗”作用。因此，这些研究将提供新的分子来探索mGluR2在可卡因依赖中的功能，并可能为治疗人类可卡因成瘾提供新的治疗药物。拟议的研究是一个高度创新的、重要的和及时的多学科项目，它利用了研究团队的专业知识，并解决了本RFA的要求。

DESCRIPTION (provided by applicant): This application entitled "Modulators of metabotropic glutamate receptor subtype 2 for cocaine dependence" is in response to RFA-DA-07-006. Cocaine addiction remains a major public health problem in the United States. To date, a safe and effective treatment for cocaine dependence has yet to be identified. Thus, there is great need to explore novel pharmacological treatments for cocaine dependence. We plan to use a multidisciplinary approach involving chemistry, in vitro pharmacology and behavioral assessment of novel compounds in rat models of cocaine dependence, withdrawal and reinstatement of cocaine-seeking behavior. Repeated cocaine exposure alters the function of Group II metabotropic glutamate receptors (mGluRs) that comprise mGluR2 and mGluR3. There have been relatively few selective compounds for mGluR2 and most of these compounds do not have good brain penetration. Here, we propose to design and synthesize new positive and negative allosteric modulators of mGluR2 that are systemically active in vivo and have good brain bioavailability (Specific Aim 1). Then, in Specific Aim 2, we will characterize these positive and negative mGluR2 allosteric modulators in in vitro assays of potency and selectivity. Further, we will assess potential off target effects of these compounds at other molecular targets in the brain. The pharmacokinetic profile and brain penetration of the most promising analogues will be evaluated in rats to facilitate selection of the best compounds for in vivo pharmacology studies. In Specific Aim 3, we will investigate the effects of mGluR2 positive and negative allosteric modulators in rat models of cocaine dependence (extended access to intravenous cocaine self-administration), reinstatement (discriminatory cue-induced reinstatement of cocaine-seeking behavior) and early withdrawal (elevations in intracranial self-stimulation thresholds during cocaine withdrawal) in rats. Additional experiments will compare the effects of the test compounds on behaviors motivated by a food reinforcer as an important aspect of drug screening for potential anti-addiction medications. It is predicted that mGluR2 positive modulators will decrease the reinforcing effects of self-administered cocaine in cocaine-"dependent" rats only, and attenuate cue-induced cocaine-seeking behavior. By contrast, administration of mGluR2 negative modulators would reverse affective signs associated with cocaine withdrawal. If mGluR2 positive or negative modulators are effective in one or several of these models, then we would achieve proof-of-concept for systemically active modulators of mGluR2 as potential novel pharmacotherapies to treat aspects of cocaine addiction in humans. Significance: The proposed studies will design and synthesize new chemical entities with high potency and selectivity for mGluR2 with good brain penetration, and potentially "therapeutic" effects in animal models of cocaine dependence. Thus, the proposed studies will provide new molecules to probe the function of mGluR2 in cocaine dependence and potentially novel therapeutic agents for the treatment of cocaine addiction in humans. The proposed research is a highly innovative, significant and timely multidisciplinary project that draws on the expertise of the research team and addresses the requirements of this RFA.