Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.

ABSTRACT: Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu₅) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu₅ allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation. To establish whether negative allosteric modulators (NAMs) engender similar bias, we rigorously characterized the pharmacology of eight diverse mGlu₅ NAMs. Radioligand inhibition binding studies revealed novel modes of interaction with mGlu₅ for select NAMs, with biphasic or incomplete inhibition of the

SUBMITTER: Sengmany K 

PROVIDER: S-EPMC6420870 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature