Discovery and Optimization of Selective Negative Allosteric Modulators of mGluR3

mGluR3 选择性负变构调节剂的发现和优化

基本信息

批准号：
8726488
负责人：
P Jeffrey Conn
金额：
$ 39万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8726488
关键词：
Address Adenosine Adenosine A1 Receptor Agonist Animal Model Animals Antidepressive Agents Area Astrocytes Brain Diseases Cells Cognition Communication Communities Equilibrium Excretory function Family G-Protein-Coupled Receptors Glutamates Goals Hippocampus (Brain)Impaired cognition Impairment Individual Knockout Mice Lead Learning Libraries Ligands Long-Term Potentiation Major Depressive Disorder Mediating Memory Mental Depression Metabolism Metabotropic Glutamate Receptors Modeling Mus Neuraxis Neurologic Neurons Neurotransmitter Receptor Patients Performance Pharmaceutical Chemistry Pharmaceutical Preparations Property Regulation Relative (related person)Reporting Research Role Series Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Toxic effect absorption beta-adrenergic receptor cognitive function improved in vivo inhibitor/antagonist interest lead series metabotropic glutamate receptor 2 metabotropic glutamate receptor 3 morris water maze new therapeutic target novel novel strategies preclinical study process optimization receptor response scaffold tool transmission process

项目摘要

DESCRIPTION (provided by applicant): The metabotropic glutamate receptors (mGluRs) have attracted considerable interest as novel therapeutic targets for multiple neurological and psychiatric conditions. Among the least studied of the eight subtypes of the mGluR family is mGluR3, where selective ligands have yet to be identified. In spite of this limitation, we have made significant progress in elucidating the roles and functions attributable to mGluR3, including a novel role for mGluR3 in regulating hippocampal function. Specifically, we have shown that group II mGluRs (mGluR2 and mGluR3) participate in a novel form of glial-neuronal communication in the hippocampus in which activation of mGluRs on astrocytes leads to release of adenosine and reduction of glutamate release from neighboring glutamate synapses. We postulate that this astrocytic response is mediated by the mGluR3 subtype and that activation of mGluR3 could impair hippocampal LTP. These results lead us to hypothesize that selective antagonists of mGluR3 could have cognition-enhancing effects. Prior studies with mGluR2/3 antagonists using both wild-type and mGluR2 knockout mice in the Morris water maze, a model of spatial learning that depends on normal hippocampal function, are consistent with mGluR3 functioning as the predominant group II mGluR subtype responsible for the cognition-enhancing effects seen with group II mGluR antagonists. Additionally, exciting new preclinical studies reveal that group II antagonists have robust efficacy in multiple animal models that predict antidepressant activity. Highly selective antagonists that are suitable for use in animal models are needed in order to better understand the respective roles of mGluR2 and mGluR3 in these studies. In addition to our multiple series of group II mGluR antagonists, we have recently discovered a series of compounds that are selective antagonists of mGluR3. Importantly, these new selective antagonists are from a chemotype that has previously delivered efficacious CNS tool compounds in the past. These selective compounds offer an unprecedented opportunity to systematically test the hypotheses presented above. In order to accomplish our goals we will optimize our compounds such that the resultant probe will possess the balance of properties required to make it a highly valuable tool to the research community. The optimization process will involve an iterative medicinal chemistry library approach focused not only on potency and selectivity, but a number of DMPK parameters associated with CNS exposure. Using our selective antagonists of mGluR3, along with mGluR3 knockout mice, we plan to rigorously test the hypothesis that blockade of mGluR3 inhibits group II mGluR-mediated astrocytic-neuronal communication in hippocampal area CA1. In addition, we will test the hypothesis that coactivation of mGluR3 and bARs leads to an impairment of hippocampal LTP. Finally, we will examine our optimized compounds in efficacy models where mGluR2/3 antagonists have been shown to have cognition-enhancing and antidepressant-like effects in order to elucidate the respective roles of each receptor.

描述（由申请人提供）：代谢型谷氨酸受体（MGLURS）引起了人们对多种神经系统和精神病疾病的新型治疗靶标的非常兴趣。 MGLUR3是MGLUR家族的八个子类型中研究最少的研究中，尚未确定选择性配体。尽管有这种限制，但我们在阐明归因于MGLUR3的作用和功能方面取得了重大进展，包括MGLUR3在调节海马功能中的新作用。具体而言，我们已经表明，II组MGLUR（MGLUR2和MGLUR3）参与了海马中的新型神经神经元通信形式，在海马中，MGLURS在星形胶质细胞上的激活会导致腺苷上释放腺苷的释放，并从邻近的邻近的谷氨酸谷氨酸合成中释放谷氨酸。我们假设这种星形胶质细胞反应是由MGLUR3亚型介导的，并且MGLUR3的激活可能会损害海马LTP。这些结果使我们假设MGLUR3的选择性拮抗剂可能具有认知增强作用。先前对MGLUR2/3拮抗剂使用野生型和MGLUR2基因敲除小鼠在Morris Water Maze中进行的研究，这是一种取决于正常海马功能的空间学习模型，与MGLUR3一致，与MGLUR 3的功能相一致，该模型作为II MGLUR组的主要MGLUR子类型，负责对认知效应的构成效应。此外，令人兴奋的新临床前研究表明，II组拮抗剂在预测抗抑郁活性的多种动物模型中具有强大的效果。适合使用的高度选择性拮抗剂在动物模型中，为了更好地了解MGLUR2和MGLUR3在这些研究中的各自作用。除了我们的多个II组MGLUR拮抗剂外，我们最近还发现了一系列MGLUR3选择性拮抗剂的化合物。重要的是，这些新的选择性拮抗剂来自以前在过去提供有效的CNS工具化合物的化学型。这些选择性化合物为系统地测试上述假设提供了前所未有的机会。为了实现我们的目标，我们将优化化合物，以使最终的探测器将拥有使其成为研究社区高度有价值的工具所需的财产平衡。优化过程将涉及迭代药物化学文库方法不仅侧重于效力和选择性，而且还集中在与CNS暴露相关的许多DMPK参数上。我们使用MGLUR3的选择性拮抗剂以及MGLUR3基因敲除小鼠，计划严格检验以下假设：封锁MGLUR3抑制了II组MGLUR介导的海马区域CA1中的MGLUR介导的星形胶质细胞 - 神经元通信。此外，我们将检验以下假设：MGLUR3和棒的共激活导致海马LTP的损害。最后，我们将检查在功效模型中的优化化合物，其中MGLUR2/3拮抗剂已被证明具有认知增强和抗抑郁药样作用，以阐明每个受体的各自作用。