Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery.

ABSTRACT: Allosteric modulators, that exhibit no intrinsic agonist activity, offer the advantage of spatial and temporal fine-tuning of endogenous agonist activity, allowing the potential for increased selectivity, reduced adverse effects and improved clinical outcomes. Some allosteric ligands can differentially activate and/or modulate distinct signaling pathways arising from the same receptor, phenomena referred to as 'biased agonism' and 'biased modulation'. Emerging evidence for CNS disorders with glutamatergic dysfunction suggests the metabotropic glutamate receptor subtype 5 (mGlu₅) is a promising target. Current mGlu₅ allosteric modulators have largely been classified based on modulation of intracellular calcium (iCa²⁺) responses to orthosteric agonists alone.

SUBMITTER: Sengmany K 

PROVIDER: S-EPMC5217481 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature