title: Neurophysiological signals as potential translatable biomarkers for modulation of metabotropic glutamate 5 receptors.
abstract: The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson's disease and neuropathic pain. The present study evaluated the effects of the mGluR5 negative allosteric modulators (NAMs) 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone (GRN-529) and methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate (AFQ056) on polysomnographic (PSG) and quantitative electroencephalographic (qEEG) measures in freely moving rats. Furthermore, the anxiolytic profile of GRN-529 was characterized in anesthetized rats by measuring stimulation-induced hippocampal theta oscillation. The present findings demonstrate that inhibition of mGluR5 via its allosteric site profoundly modulates high-level neuronal network activities as indicated by changes in sleep-wake activity and power distribution of qEEG. Both GRN-529 and AFQ056 reduced the total time spent in rapid-eye movement with AFQ056 producing a significant increase in wakefulness at the highest dose tested. Additionally, qEEG revealed significant compound-induced increases in delta power concomitant with more subtle decreases in theta and alpha band power. Receptor occupancy (RO) studies revealed that GRN-529 and AFQ056 at all doses resulted in over 45% mGluR5 occupancy. Furthermore, GRN-529 dose-dependently decreased elicited hippocampal theta frequency, consistent with previous findings using clinically active anxiolytic compounds. The described changes in neurophysiological signals identified in freely moving rats may be considered suitable translational biomarkers for the clinical evaluation of mGluR5 NAMs.
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Harvey
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Siok
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kiss
authors.affiliation: Research Statistics, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Volfson
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Grimwood
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Metabolism, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Shaffer
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA. Electronic address: mihaly.hajos@yale.edu.
authors.forename: M
authors.initials: M
authors.lastname: Hajós
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000494:pharmacology; D005133:Eye Movements / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; C576999:GRN-529; D007211:Indoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D014316:Tritium; C121465:6-methyl-2-(phenylethynyl)pyridine; C581397:mavoglurant
keywords: 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone; AFQ056; AP; Anterior Posterior; Anxiety; DV; Dorsal Ventral; EEG; EMG; FFT; Fast-Fourier transform; GRN-529; JVC; LLOQ; N-Methyl-D-aspartate; NAM; NMDA; NREM; PET; PSG; Polysomnography; Quantitative electroencephalography; REM; RO; Rat; S-R; USP; United States Pharmacopeia; electroencephalogram; electromyogram; jugular vein-cannulated; lower limit of quantification; mGluR5; metabotropic glutamate receptor subtype 5; methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate; nPO; negative allosteric modulator; non REM sleep; nucleus Pontis Oralis; polysomnography; positron emission tomography; qEEG; quantitative electroencephalogram; rapid eye movement; receptor occupancy; simulation response; standard deviation of the EMG amplitude; σ(emg)