title: Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on L: -DOPA-induced dyskinesia.
abstract: Subtype 5 metabotropic glutamate receptors (mGluR5) are abundant in the basal ganglia, amygdala, septum, hippocampus, peripheral sensory neurones and dorsal horn of the spinal cord. Thus, mGluR5 has been implicated in central processes underlying movement control, emotion, learning, and nociception. Different negative allosteric modulators (NAMs) of mGluR5 were repeatedly shown to be efficacious in models of L: -DOPA-induced dyskinesia (LID), anxiety, and some forms of pain. MRZ-8676 (6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one) is a novel proprietary, selective, orally bioavailable mGluR5 NAM. MRZ-8676 (8.33, 25 and 75 mg/kg) showed a high efficacy in the rat model of LID, with the maximal effect size reaching ~80%. The antidyskinetic effects of MRZ-8676 (75 mg/kg) did not show tolerance as assessed after repetitive (6 days) treatment. MRZ-8676 (25 or 75 mg/kg) demonstrated moderate efficacy in two rat models of anxiety-contextual fear conditioning and the elevated plus maze. MRZ-8676 (25 mg/kg) was also effective in the formalin test, a rat model of persistent pain. The efficacious doses of MRZ-8676 did not produce any detrimental effects on motor performance of rats as determined by means of automated open field and rotarod. However, high doses of MRZ-8676 (75 or 150 mg/kg) disrupted learning in an aversive learning paradigm of the contextual fear conditioning test. In conclusion, MRZ-8676 is a new investigational agent with an efficacy profile similar to the widely published reference mGluR5 NAMs. The drug was demonstrated to possess a superior antidyskinetic efficacy with a sufficient therapeutic window. MRZ-8676 has also therapeutic potential as an anxiolytic and analgesic drug.
authors.affiliation: In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany. andrzej.dekundy@merz.de
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dekundy
authors.forename: Andreas
authors.initials: A
authors.lastname: Gravius
authors.forename: Mirko
authors.initials: M
authors.lastname: Hechenberger
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Pietraszek
authors.forename: Jens
authors.initials: J
authors.lastname: Nagel
authors.forename: Carsten
authors.initials: C
authors.lastname: Tober
authors.forename: Martine
authors.initials: M
authors.lastname: van der Elst
authors.forename: Flora
authors.initials: F
authors.lastname: Mela
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Parsons
authors.forename: Wojciech
authors.initials: W
authors.lastname: Danysz
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000494:Allosteric Regulation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000627:therapeutic use*; D005239:Fear / Q000187:drug effects; D066298:In Vitro Techniques; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010147:Pain Measurement; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy; D010848:Picolinic Acids / Q000008:administration & dosage; D011597:Psychomotor Performance / Q000187:drug effects; D015363:Quinolones / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045442:Rotarod Performance Test; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors
chemical_list: C571008:6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one; D018663:Adrenergic Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D008996:Monoamine Oxidase Inhibitors; D010848:Picolinic Acids; D015363:Quinolones; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C059303:lazabemide; D007980:Levodopa; D016627:Oxidopamine; D002118:Calcium