mGluR5 allosteric potentiators:In Vivo Characterization

mGluR5 变构增强剂：体内表征

基本信息

批准号：
7388281
负责人：
Carrie Kimberly Jones
金额：
$ 1.96万
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：
2006-12-01 至 2008-04-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388281
关键词：
Address Agonist Allosteric Site Alzheimer&apos s Disease Antipsychotic Agents Behavioral Behavioral Model Benzamides Binding Sites Blood - brain barrier anatomy Brain Brain region Cell physiology Cells Chemicals Cognition Data Disease Disruption Dose Electrophysiology (science)Epilepsy Evaluation Functional disorder Glutamates Half-Life Hippocampus (Brain)Huntington Disease Impaired cognition Individual Knock-out Laboratories Ligands Mediating Metabotropic Glutamate Receptors Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Parkinson Disease Penetrance Pharmacology Physiological Positioning Attribute Property Pyramidal Cells Radial Rattus Rodent Rodent Model Schizophrenia Series Short-Term Memory Site Slice Solubility Symptoms Synapses Techniques Testing Time Upper arm base design diphenyl in vivo neuropsychiatry novel strategies patch clamp predictive modeling prepulse inhibition pyridine receptor response

项目摘要

DESCRIPTION (provided by applicant): Recent studies in Dr. Conn's laboratory suggest that potentiators of the metabotropic glutamate receptor mGluR5 may provide a novel approach for the treatment of the psychotic symptoms and cognitive impairments observed in individuals with schizophrenia. In particular, these mGluR5 potentiators do not activate the mGluR5 receptor directly, but dramatically potentiate the response to glutamate. The proposal involves the characterization of the cellular physiology, functional brain penetrance and in vivo efficacy of the selective mGluR5 allosteric potentiator CDPPB. In the initial studies, we will determine whether CDPPB potentiates synaptic responses to mGluR5 activation in the pyramidal cells of the CA1 region of the hippocampus, a brain region implicated in the pathophysiology of schizophrenia. Next we will determine the in vivo receptor occupancy of CDPPB in order to understand the functional brain penetrance of this compound. Based on these occupancy studies, we will select doses and time points for further characterization of CDPPB in several behavioral models predictive of antipsychotic activity and enhancement of cognition.

描述（由申请人提供）：CONN博士实验室的最新研究表明，代谢性谷氨酸受体MGLUR5的增强剂可能为治疗精神病患者观察到的精神病症状和认知障碍提供了一种新的方法。特别是，这些MGLUR5电位器不会直接激活MGLUR5受体，而是会显着增强对谷氨酸的反应。该建议涉及细胞生理学的表征，功能性脑渗透性以及选择性MGLUR5变构增强剂CDPPB的体内功效。在最初的研究中，我们将确定CDPPB是否会增强对海马CA1区域的锥体细胞中MGLUR5激活的突触反应，这是脑部区域，该大脑区域与精神分裂症的病理生理有关。接下来，我们将确定CDPPB的体内受体占用率，以了解该化合物的功能性脑渗透。基于这些占用研究，我们将在几种可预测抗精神病药活性和认知增强的行为模型中选择剂量和时间点，以进一步表征CDPPB。