Pharmacological characterisation of allosteric modulators at human mGlu5

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The metabotropic glutamate receptor 5 (mGlu 5 ) 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 5 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 5 function. While mGlu 5 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 5 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 5 PAMs, NAMs and NALs on human mGlu 5 activity using radioligand binding, intracellular calcium (iCa 2+ ) mobilisation and inositol monophosphate (IP 1 ) accumulation assays. By comparing to published and newly generated data for rat mGlu 5 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 5. Together, these data highlight the importance of systematic evaluation of mGlu 5 allosteric ligand activity at human mGlu 5 to improve drug design and overcome potential barriers to translatability to clinical settings.

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