Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-0697, USA.
Biol Psychiatry. 2013 Mar 15;73(6):501-9. doi: 10.1016/j.biopsych.2012.09.012. Epub 2012 Nov 7.
Metabotropic glutamate receptor subtype 5 (mGlu5) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu5 PAMs do not activate mGlu5 directly but selectively potentiate activation of mGlu5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu5 activation and achieving optimal in vivo effects.
Using specially engineered mGlu5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate.
Both in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations.
Loss of the absolute dependence of mGlu5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia.
代谢型谷氨酸受体 5 型（mGlu5）激动剂已成为治疗精神分裂症的一种新方法。mGlu5 的正变构调节剂（PAMs）引起了极大的关注，并推动了主要的药物发现工作。尽管 mGlu5 PAMs 在精神分裂症的临床前模型中具有强大的疗效，但初步报告表明这些化合物可能会引起癫痫发作。典型的 mGlu5 PAMs 不会直接激活 mGlu5，而是选择性增强谷氨酸对 mGlu5 的激活。这种机制对于维持 mGlu5 激活的正常活动依赖性并实现最佳的体内效果可能至关重要。
使用专门设计的 mGlu5 细胞系，该细胞系在变构和 orthosteric 结合位点中包含点突变，以及脑片电生理学和体内脑电图和行为药理学，我们发现一些 mGlu5 PAMs 在没有谷氨酸的情况下具有内在的变构激动剂活性。
体外突变和体内药理学研究均表明，VU0422465 是一种激动剂 PAM，可在啮齿动物中诱导癫痫样活动和行为性惊厥。相比之下，VU0361747 是一种优化的 mGlu5 PAMs，可消除变构激动剂活性，具有强大的体内疗效，并且在产生高脑浓度的剂量下不会引起不良反应。
mGlu5 PAMs 的活性对谷氨酸释放的绝对依赖性丧失可能导致严重的不良反应。发现密切相关的 mGlu5 PAMs 可能在其内在激动剂活性方面存在差异，这为推进这些分子通过临床开发用于治疗精神分裂症提供了至关重要的新见解。
