Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

中文翻译：

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XAP044 对代谢型谷氨酸 7 受体 Venus Flytrap 结构域的作用模式揭示了新的抑制位点

代谢型谷氨酸 (mGlu) 受体在调节大脑中的大多数突触中发挥着关键作用。 mGlu7 受体抑制突触前神经递质释放，为创伤后应激障碍或癫痫提供治疗可能性。筛选活动提供了 mGlu7 特异性变构调节剂作为抑制剂XAP044（Gee 等人J. Biol. Chem. 2014）。与其他 mGlu 受体变构调节剂相反，XAP044不在跨膜结构域中结合，而是与 mGlu7 受体的胞外结构域结合，而不是在正构位点结合。在这里，我们结合衍生物的合成、建模和对接实验以及诱变确定了XAP044的作用模式。我们提出了这些抑制剂的独特作用模式，防止维纳斯捕蝇草激动剂结合域的关闭。在充当L-AP4的非竞争性拮抗剂的同时，XAP044及其衍生物充当LSP4-2022的明显竞争性拮抗剂。这些数据揭示了更有效的XAP044类似物和靶向 mGluR 的新可能性。