title: 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 mGlu5allosteric modulators have largely been classified based on modulation of intracellular calcium (iCa2+) responses to orthosteric agonists alone. We assessed eight mGlu5allosteric modulators previously classified as mGlu5PAMs or PAM-agonists representing four distinct chemotypes across multiple measures of receptor activity, to explore their potential for engendering biased agonism and/or modulation. Relative to the reference orthosteric agonist, DHPG, the eight allosteric ligands exhibited distinct biased agonism fingerprints for iCa2+mobilization, IP1accumulation and ERK1/2 phosphorylation in HEK293A cells stably expressing mGlu5and in cortical neuron cultures. VU0424465, DPFE and VU0409551 displayed the most disparate biased signaling fingerprints in both HEK293A cells and cortical neurons that may account for the marked differences observed previously for these ligands in vivo. Select mGlu5allosteric ligands also showed 'probe dependence' with respect to their cooperativity with different orthosteric agonists, as well as biased modulation for the magnitude of positive cooperativity observed. Unappreciated biased agonism and modulation may contribute to unanticipated effects (both therapeutic and adverse) when translating from recombinant systems to preclinical models. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC, Australia. Electronic address: Kathy.sengmany@monash.edu.
authors.forename: Kathy
authors.initials: K
authors.lastname: Sengmany
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC, Australia. Electronic address: junaidsingh1@gmail.com.
authors.forename: Junaid
authors.initials: J
authors.lastname: Singh
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC, Australia. Electronic address: greg.stewart@monash.edu.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Stewart
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: jeff.conn@vanderbilt.edu.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC, Australia. Electronic address: arthur.christopoulos@monash.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC, Australia. Electronic address: karen.gregory@monash.edu.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Gregory
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods / Q000639:trends*; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; D064529:Receptor, Metabotropic Glutamate 5
keywords: Biased agonism; CDPPB (PubChem CID: 11245456); DHPG (PubChem CID: 108001); DPFE (PubChem CID: 16663278); Glutamate (L-glutamic acid PubChem CID: 33032); Metabotropic glutamate receptor 5; Positive allosteric modulator; Stimulus bias; VU0360172 (PubChem CID: 53318624); VU0403602 (PubChem CID: 53384878); VU0405398 (PubChem CID: 70789303); VU0424465 (PubChem CID: 53384864); VU29 (PubChem CID: 11610682)