Discovery and Optimization of Selective Negative Allosteric Modulators of mGluR3

描述（由申请人提供）：代谢型谷氨酸受体（mGluR）作为多种神经和精神疾病的新型治疗靶点引起了相当大的兴趣。 mGluR 家族八个亚型中研究最少的是 mGluR3，其选择性配体尚未确定。尽管存在这一局限性，我们在阐明 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。具体来说，我们已经证明，II 组 mGluR（mGluR2 和 mGluR3）参与海马中一种新形式的胶质神经元通讯，其中星形胶质细胞上 mGluR 的激活导致腺苷释放并减少邻近谷氨酸突触的谷氨酸释放。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。这些结果使我们推测 mGluR3 的选择性拮抗剂可能具有认知增强作用。之前在 Morris 水迷宫（一种依赖于正常海马功能的空间学习模型）中使用野生型和 mGluR2 敲除小鼠进行的 mGluR2/3 拮抗剂研究与 mGluR3 作为主要的 II 组 mGluR 亚型的作用一致，该亚型负责 II 组 mGluR 拮抗剂所见的认知增强作用。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功效。适合使用的高选择性拮抗剂 为了更好地了解 mGluR2 和 mGluR3 在这些研究中各自的作用，需要在动物模型中进行研究。除了我们的多个系列 II 组 mGluR 拮抗剂外，我们最近还发现了一系列选择性 mGluR3 拮抗剂化合物。重要的是，这些新的选择性拮抗剂来自过去曾提供有效的中枢神经系统工具化合物的化学型。这些选择性化合物为系统地检验上述假设提供了前所未有的机会。为了实现我们的目标，我们将优化我们的化合物，使所得探针具有所需的性能平衡，使其成为研究界非常有价值的工具。优化过程将涉及迭代药物化学库方法，该方法不仅关注效力和选择性，还关注与中枢神经系统暴露相关的许多 DMPK 参数。使用我们的选择性 mGluR3 拮抗剂以及 mGluR3 敲除小鼠，我们计划严格测试以下假设：阻断 mGluR3 会抑制海马 CA1 区 II 组 mGluR 介导的星形胶质细胞神经元通讯。此外，我们将检验 mGluR3 和 bAR 的共激活导致海马 LTP 受损的假设。最后，我们将在功效模型中检查我们优化的化合物，其中 mGluR2/3 拮抗剂已被证明具有认知增强和抗抑郁样作用，以阐明每种受体各自的作用。

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.