Modulators of Metabotropic Glutamate Receptor Subtype 2 for Cocaine Dependence

描述(由申请人提供)：本申请名为“针对可卡因依赖的代谢型谷氨酸受体亚型2的调节剂”，是对RFA-DA-07-006的回应。在美国，可卡因成瘾仍然是一个主要的公共卫生问题。迄今为止，尚未确定安全有效的可卡因依赖治疗方法。因此，迫切需要探索治疗可卡因依赖的新的药物治疗方法。我们计划使用一种涉及化学、体外药理学和行为评估的多学科方法，在可卡因依赖、戒断和恢复可卡因寻找行为的大鼠模型中对新化合物进行评估。反复接触可卡因改变了组成mGluR2和mGluR3的第二组代谢性谷氨酸受体(MGluRs)的功能。对mGluR2有选择性的化合物相对较少，而且大多数化合物都没有很好的大脑渗透性。在这里，我们建议设计和合成新的mGluR2正负变构调节剂，这些调节剂在体内具有系统活性，并具有良好的脑生物利用度(特定目标1)。然后，在特定的目标2中，我们将在体外实验中表征这些正负的mGluR2变构调节剂的效力和选择性。此外，我们将评估这些化合物对大脑中其他分子靶点的潜在脱靶效应。将评估最有希望的类似物在大鼠体内的药代动力学和脑渗透情况，以便于选择最好的化合物进行体内药理学研究。在具体目标3中，我们将研究mGluR2正负变构调节剂在可卡因依赖(延长静脉注射可卡因自我给药)、恢复(辨别性提示诱导寻找可卡因行为的恢复)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。其他实验将比较测试化合物对食品强化剂激发的行为的影响，作为潜在抗成瘾药物药物筛选的一个重要方面。据预测，mGluR2正性调节剂只会减弱自身给药对可卡因“依赖”大鼠的增强作用，并减弱线索诱导的可卡因寻找行为。相比之下，给予mGluR2负性调节剂将逆转与可卡因戒断相关的情感体征。如果mGluR2正负调节剂在其中一个或几个模型中有效，那么我们将实现mGluR2系统活性调节剂的概念验证，作为潜在的新型药物疗法来治疗人类可卡因成瘾的各个方面。意义：拟议的研究将设计和合成新的化学实体，具有高效和选择性的mGluR2，具有良好的大脑渗透性，并在可卡因依赖的动物模型中具有潜在的“治疗”作用。因此，拟议的研究将为探索mGluR2在可卡因依赖中的功能提供新的分子，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、意义重大和及时的多学科项目，它利用了研究团队的专业知识，并满足了本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.