Role of mGluR5 positive allosteric modulators in schizophrenia

描述（由申请人提供）：本项目的目的是更深入地了解代谢型谷氨酸受体亚型5（mGluRS）的变构调节，以及该受体在精神疾病（如精神分裂症）中的作用。希望这项研究将增加越来越多的文献，这将导致更有效的精神病药物，从而改善患者的功能结果。该项目将处理两个相关的目标。首先，将评估一类新的mGluR5正变构调节剂（PAM），以检验这些化合物与受体上的新位点结合的假设。其次，将在动物模型中评价这些mGluRS PAM的功效，以检验化合物将具有抗精神病和认知增强活性的假设。精神分裂症的谷氨酸假说指出，阳性和阴性症状以及该疾病特有的认知缺陷的一个原因可能是通过N-甲基-D-谷氨酸受体（NMDAR）的信号传导的变化。已发现直接增强NMDAR功能可改善精神分裂症症状，但具有毒性作用。研究表明，mGluRS和NMDAR是紧密耦合的信号伴侣，并且mGluRS的激活可以增强海马中的NMDAR电流。因此，使用PAM激活mGluRS可以间接增强NMDAR功能，从而改善精神分裂症的症状。对于本项目的第一个目标，将使用定点诱变探索新PAM功能所必需的mGluRS结构域。抑制某些mGluRS调节剂功能的突变受体将用于确定突变体对新化合物作用的影响。基于经典受体理论的药理学方法也将用于确定PAM是否可以与配体竞争，所述配体与先前表征的MPEP位点相互作用。具体而言，Schild分析将确定中性变构配体5MPEP是否将竞争性阻断新型PAM的作用。对于第二个目标，将进行行为测定以确定这些新化合物的作用。为了评估抗精神病药物的功效，将研究化合物逆转安非他明诱导的过度运动和安非他明诱导的对声惊吓反应（PPI）前脉冲抑制的破坏的能力。接下来，将研究PAM逆转MK 801诱导的注意定势转移缺陷的能力，作为认知灵活性的量度。公共卫生相关性：目前对精神分裂症的治疗不足以治疗该病症的所有症状，尤其是阴性症状（即戒断）和认知缺陷。这项研究正在采取一种新的药理学方法来解决这个问题，并将重点放在大脑中的mGluRS受体上，该受体似乎参与调节导致精神分裂症症状的神经传递中断。

DESCRIPTION (provided by applicant): The purpose of this project is to gain a deeper understanding of allosteric modulation of the metabotropic glutamate receptor subtype 5 (mGluRS), and the role of the receptor in psychiatric disorders, such as schizophrenia. It is hoped that this research will add to a growing body of literature that will lead to more effective psychiatric medication, and thus improved functional outcomes for patients. This project will address two related objectives. First, a novel class of positive allosteric modulators (PAMs) of mGluR5 will be assessed to test the hypothesis that these compounds are binding to a novel site on the receptor. Second, the efficacy of these mGluRS PAMs will be evaluated in animal models to test the hypothesis that the compounds will have antipsychotic and cognitive-enhancing activity. The glutamate hypothesis of schizophrenia states that one cause of the positive and negative symptoms as well as cognitive deficits characteristic of the disease may be a change in signaling through the /V-methyl-D-aspartatereceptor (NMDAR). Direct enhancement of NMDAR function has been found to ameliorate schizophrenic symptoms but has toxic effects. Studies have shown that mGluRS and the NMDAR are closely coupled signaling partners, and activation of mGluRS can potentiate NMDAR current in the hippocampus. Thus activating mGluRS using PAMs can indirectly enhance NMDAR function and consequently ameliorate symptoms of schizophrenia. For the first aim of this project, the domains of mGluRS that are necessary for the function of the novel PAMs will be explored using site-directed mutagenesis. Mutant receptors that inhibit the function of certain mGluRS modulators will be used to determine the effects of the mutants on the actions of the novel compounds. Pharmacological methods based on classical receptor theory will also be used to determine whether the PAMs can compete with ligands that interact with the previously characterized MPEP site. Specifically, Schild analysis will determine whether the neutral allosteric ligand 5MPEP will competitively block the actions of the novel PAMs. For the second aim, behavioral assays will be conducted to establish the effects of these novel compounds. To evaluate antipsychotic efficacy, the ability of compounds to reverse amphetamine-induced hyperlocomotion and amphetamine-induced disruption of prepulse inhibition of the acoustic startle response (PPI) will be investigated. Next, the ability of the PAMs to reverse MK801-induced deficits in attentional set-shifting as a measure of cognitive flexibility will be studied. Public Health Relevance: Current treatment for schizophrenia is not sufficient to treat all symptoms of the disorder, especially the negative symptoms, (i.e. withdrawal) and cognitive deficits. This research is taking a novel pharmacological approach to address this problem, and will focus on the mGluRS receptor in the brain that seems to be involved in regulation of disrupted neurotransmission that leads to schizophrenic symptoms.