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。在mGluR家族的八种亚型中，研究最少的是mGluR 3，其中选择性配体尚未被鉴定。尽管存在这种局限性，但我们在阐明mGluR 3的作用和功能方面取得了重大进展，包括mGluR 3在调节海马功能中的新作用。具体而言，我们已经表明，第二组mGluRs（mGluR 2和mGluR 3）参与一种新的形式的神经胶质细胞神经元的通信在海马体中，星形胶质细胞上的mGluRs的激活导致腺苷的释放和减少谷氨酸释放从相邻的谷氨酸突触。我们推测这种星形胶质细胞反应是由mGluR 3亚型介导的，并且mGluR 3的激活可以损害海马LTP。这些结果使我们假设mGluR 3的选择性拮抗剂可能具有认知增强作用。先前在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mGluR 2敲除小鼠进行的mGluR 2/3拮抗剂研究与mGluR 3作为主要的II组mGluR亚型发挥作用一致，后者负责II组mGluR拮抗剂的认知增强作用。此外，令人兴奋的新的临床前研究表明，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疗效。适合使用的高选择性拮抗剂 为了更好地理解mGluR 2和mGluR 3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的II组mGluR拮抗剂，我们最近发现了一系列的化合物，是mGluR 3的选择性拮抗剂。重要的是，这些新的选择性拮抗剂来自过去已经递送有效CNS工具化合物的化学型。这些选择性化合物提供了一个前所未有的机会，系统地测试上述假设。为了实现我们的目标，我们将优化我们的化合物，使所得的探针将拥有所需的性能平衡，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，不仅关注效价和选择性，还关注与CNS暴露相关的许多DMPK参数。使用我们的mGluR 3选择性拮抗剂，沿着与mGluR 3敲除小鼠，我们计划严格测试的假设，即阻断mGluR 3抑制II组mGluR介导的星形胶质细胞-神经元通信在海马CA 1区。此外，我们将测试的假设，mGluR 3和bARs共激活导致海马LTP的损害。最后，我们将研究我们的优化化合物的功效模型，其中mGluR 2/3拮抗剂已被证明具有认知增强和抗抑郁样作用，以阐明每个受体的各自作用。

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.