caa a22 4500 445376589 CHVBK 20180317143004.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00702-010-0526-0 doi (NATIONALLICENCE)springer-10.1007/s00702-010-0526-0 Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on l -DOPA-induced dyskinesia [Elektronische Daten] [Andrzej Dekundy, Andreas Gravius, Mirko Hechenberger, Małgorzata Pietraszek, Jens Nagel, Carsten Tober, Martine van der Elst, Flora Mela, Christopher Parsons, Wojciech Danysz] 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 75mg/kg) showed a high efficacy in the rat model of LID, with the maximal effect size reaching ~80%. The antidyskinetic effects of MRZ-8676 (75mg/kg) did not show tolerance as assessed after repetitive (6days) treatment. MRZ-8676 (25 or 75mg/kg) demonstrated moderate efficacy in two rat models of anxiety-contextual fear conditioning and the elevated plus maze. MRZ-8676 (25mg/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 150mg/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. Springer-Verlag, 2010 mGluR5 nationallicence Microdialysis nationallicence Levodopa-induced dyskinesia nationallicence Pain nationallicence Anxiety nationallicence Dekundy Andrzej In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Gravius Andreas In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Hechenberger Mirko In Vitro Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Pietraszek Małgorzata In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Nagel Jens In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Tober Carsten Rent-a-lab, Aspenhaustr. 25, 72770, Reutlingen, Germany aut van der Elst Martine In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Mela Flora In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Parsons Christopher In Vitro Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Danysz Wojciech In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut Journal of Neural Transmission Springer Vienna 118/12(2011-12-01), 1703-1716 0300-9564 118:12<1703 2011 118 702 https://doi.org/10.1007/s00702-010-0526-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-010-0526-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Dekundy Andrzej In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Gravius Andreas In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Hechenberger Mirko In Vitro Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Pietraszek Małgorzata In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Nagel Jens In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Tober Carsten Rent-a-lab, Aspenhaustr. 25, 72770, Reutlingen, Germany aut NATIONALLICENCE 700 1- van der Elst Martine In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Mela Flora In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Parsons Christopher In Vitro Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 700 1- Danysz Wojciech In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/12(2011-12-01), 1703-1716 0300-9564 118:12<1703 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer