Razzak Muhammad Abdur, Tran Kevin, McCague Roisin, Sengmany Kathy, Kos Jackson, Langiu Monica, Li Bohan, Hellyer Shane D, Gregory Karen J
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Biochem Pharmacol. 2025 Sep;239:117030. doi: 10.1016/j.bcp.2025.117030. Epub 2025 Jun 6.
The metabotropic glutamate receptor 5 (mGlu) is a Class C G protein-coupled receptor, ubiquitously expressed throughout the central nervous system (CNS). With major roles in cognition, learning and memory, mGlu dysfunction is linked with numerous neurodegenerative and neuropsychiatric disorders, representing a viable therapeutic target. Allosteric modulators bind topographically distinct sites from glutamate and other orthosteric agonists and enhance (positive allosteric modulators, PAMs), inhibit (negative allosteric modulators, NAMs) or do not effect (neutral allosteric ligands, NALs) mGlu function. While mGlu modulators have efficacy in in vivo rodent models of CNS disorders, none have been approved for human use. We hypothesise preclinical optimisation using non-human pharmacological data may contribute to translational failures, as functional studies are predominantly performed using rat mGlu and non-human brain neuronal cultures. Here we are the first to systematically assess and quantify the impact of eleven chemically and pharmacologically diverse mGlu PAMs, NAMs and NALs on human mGlu activity using radioligand binding, intracellular calcium (iCa) mobilisation and inositol monophosphate (IP) accumulation assays. By comparing to published and newly generated data for rat mGlu we show that while modulator pharmacology is relatively consistent across species, ligand dependent species differences in allosteric modulator affinity, cooperativity and probe dependence are evident. Additionally, we report PAM-dependent effects on orthosteric agonist kinetic profiles at human mGlu Together, these data highlight the importance of systematic evaluation of mGlu allosteric ligand activity at human mGlu to improve drug design and overcome potential barriers to translatability to clinical settings.
代谢型谷氨酸受体5（mGlu）是C类G蛋白偶联受体，在整个中枢神经系统（CNS）中普遍表达。mGlu在认知、学习和记忆中起主要作用，其功能障碍与多种神经退行性疾病和神经精神疾病有关，是一个可行的治疗靶点。变构调节剂与谷氨酸和其他正构激动剂在拓扑结构上不同的位点结合，增强（正变构调节剂，PAMs）、抑制（负变构调节剂，NAMs）或不影响（中性变构配体，NALs）mGlu功能。虽然mGlu调节剂在中枢神经系统疾病的体内啮齿动物模型中有效，但尚无一种被批准用于人类。我们假设，由于功能研究主要使用大鼠mGlu和非人类脑神经元培养物，利用非人类药理学数据进行临床前优化可能导致转化失败。在这里，我们首次使用放射性配体结合、细胞内钙（iCa）动员和肌醇单磷酸（IP）积累测定法，系统地评估和量化了11种化学和药理学上不同的mGlu PAMs、NAMs和NALs对人类mGlu活性的影响。通过与已发表的和新生成的大鼠mGlu数据进行比较，我们发现虽然调节剂药理学在不同物种间相对一致，但变构调节剂亲和力、协同性和探针依赖性方面的配体依赖性物种差异是明显的。此外，我们报告了PAM对人类mGlu正构激动剂动力学曲线的依赖性影响。总之，这些数据强调了系统评估人类mGlu变构配体活性对改进药物设计和克服向临床环境转化的潜在障碍的重要性。
