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Allosteric Ligands of Metabotropic Glutamate Receptor 5 Have Biased Agonism and Cooperativity
Author(s) -
Gregory Karen,
Sengmany Kathy,
Singh Junaidjit,
Christopoulos Arthur
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.772.17
Subject(s) - allosteric regulation , allosteric modulator , metabotropic glutamate receptor , agonist , pharmacology , metabotropic glutamate receptor 5 , cooperativity , desensitization (medicine) , chemistry , glutamate receptor , receptor , biophysics , microbiology and biotechnology , biology , biochemistry
Metabotropic glutamate receptor subtype 5 (mGlu 5 ) is a G protein‐coupled receptor that has emerged as an exciting new therapeutic target for schizophrenia and depression. Drugs targeting mGlu 5, particularly allosteric modulators, have promising preclinical profiles; however, may also be associated with adverse effects. We hypothesise that potential on‐target adverse effects of certain allosteric modulators are related to unappreciated stimulus‐bias profiles. We investigated whether allosteric modulators from diverse scaffolds show differential modulation of distinct mGlu5 signalling pathways and receptor regulation processes. Allosteric modulator pharmacology of ten chemical series was assessed following both acute and prolonged exposure to mGlu 5 . Signalling endpoints included intracellular Ca2+ mobilization (iCa2+), inositol phosphate accumulation (IP), kinase phosphorylation and cell impedance. VU0424465, a full allosteric agonist for both iCa2+ and IP, exhibited positive cooperativity with glutamate in mediating iCa2+, but was neutral with respect to IP. Conversely, VU0360172 lacked intrinsic efficacy for iCa2+, was a partial agonist for IP, had positive cooperativity with glutamate in iCa2+ and was neutral for IP. Prolonged mGlu 5 exposure to VU0424465 resulted in robust desensitization of iCa2+, whereas VU0360172 caused a moderate degree of desensitization. In contrast, greater desensitization was evident with VU0360172 compared to VU0424465 for IP. These studies will help to elucidate mechanisms of on‐target mGlu 5 modulator adverse effects. Further, establishing a “biased modulation fingerprint” can provide a framework for future novel biased modulator discovery.