title: Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression.
abstract: Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research, 700 Main Street, Cambridge, MA 02139, USA. Zoe.Hughes@Pfizer.com
authors.forename: Z A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: S J
authors.initials: SJ
authors.lastname: Neal
authors.forename: D L
authors.initials: DL
authors.lastname: Smith
authors.forename: S J
authors.initials: SJ
authors.lastname: Sukoff Rizzo
authors.forename: C M
authors.initials: CM
authors.lastname: Pulicicchio
authors.forename: S
authors.initials: S
authors.lastname: Lotarski
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.forename: J M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: J
authors.initials: J
authors.lastname: Brennan
authors.forename: M
authors.initials: M
authors.lastname: Olsen
authors.forename: C N
authors.initials: CN
authors.lastname: Bender
authors.forename: E
authors.initials: E
authors.lastname: Kouranova
authors.forename: T H
authors.initials: TH
authors.lastname: Andree
authors.forename: J E
authors.initials: JE
authors.lastname: Harrison
authors.forename: G T
authors.initials: GT
authors.lastname: Whiteside
authors.forename: D
authors.initials: D
authors.lastname: Springer
authors.forename: S V
authors.initials: SV
authors.lastname: O'Neil
authors.forename: S K
authors.initials: SK
authors.lastname: Leonard
authors.forename: L E
authors.initials: LE
authors.lastname: Schechter
authors.forename: J
authors.initials: J
authors.lastname: Dunlop
authors.forename: S
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: R H
authors.initials: RH
authors.lastname: Ring
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects* / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000523:psychology; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
chemical_list: D000700:Analgesics; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; C576999:GRN-529; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D018698:Glutamic Acid; D002118:Calcium; C108823:metabotropic glutamate receptor 4