Skip to main content
SpringerLink
Log in

Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on l-DOPA-induced dyskinesia

  • Basic Neurosciences, Genetics and Immunology - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Andersson M, Hilbertson A, Cenci MA (1999) Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease. Neurobiol Dis 6:461–474

    Article  PubMed  CAS  Google Scholar 

  • Berg D, Godau J, Trenkwalder C, Eggert A, Csoti I, Storch A, Gasparini F, Hariry S, Vandermeulebroecke M, Johns D, Gomez-Mancilla B (2010) AFQ056 treatment of severe levodopa-induced dyskinesias: proof of concept study. Mov Disord 25(Suppl. 2):S290

    Google Scholar 

  • Blanchet PJ, Konitsiotis S, Chase TN (1998) Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys. Mov Disord 13:798–802

    Article  PubMed  CAS  Google Scholar 

  • Cenci MA, Lee CS, Bjorklund A (1998) l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur J Neurosci 10:2694–2706

    Article  PubMed  CAS  Google Scholar 

  • Coderre TJ, Yashpal K, Henry JL (1994) Specific contribution of lumbar spinal mechanisms to persistent nociceptive responses in the formalin test. Neuroreport 5:1337–1340

    PubMed  CAS  Google Scholar 

  • Conn PJ, Battaglia G, Marino MJ, Nicoletti F (2005) Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat Rev Neurosci 6:787–798

    Article  PubMed  CAS  Google Scholar 

  • Dekundy A, Pietraszek M, Schaefer D, Cenci MA, Danysz W (2006) Effects of group I metabotropic glutamate receptors blockade in experimental models of Parkinson’s disease. Brain Res Bull 69:318–326

    Article  PubMed  CAS  Google Scholar 

  • Dekundy A, Lundblad M, Danysz W, Cenci MA (2007) Modulation of l-DOPA-induced abnormal involuntary movements by clinically tested compounds: further validation of the rat dyskinesia model. Behav Brain Res 179:76–89

    Article  PubMed  CAS  Google Scholar 

  • Dolan S, Nolan AM (2000) Behavioural evidence supporting a differential role for group I and II metabotropic glutamate receptors in spinal nociceptive transmission. Neuropharmacology 39:1132–1138

    Article  PubMed  CAS  Google Scholar 

  • Eisenberg E, Vos BP, Strassman AM (1996) The peripheral antinociceptive effect of morphine in a rat model of facial pain. Neuroscience 72:519–525

    Article  PubMed  CAS  Google Scholar 

  • Fisher K, Coderre TJ (1996) The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception. Pain 68:255–263

    Article  PubMed  CAS  Google Scholar 

  • Fisher K, Coderre TJ (1998) Hyperalgesia and allodynia induced by intrathecal (RS)-dihydroxyphenylglycine in rats. Neuroreport 9:1169–1172

    Article  PubMed  CAS  Google Scholar 

  • Friedmann CTH, Davis LJ, Ciccone PE, Rubin RT (1980) Phase II double blind controlled study of a new anxiolytic, fenobam (McN-3377) vs. placebo. Curr Ther Res 27:144–151

    Google Scholar 

  • Glowinski J, Iverson LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem 13:655–662

    Article  PubMed  CAS  Google Scholar 

  • Gravius A, Dekundy A, Nagel J, More L, Pietraszek M, Danysz W (2008) Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats. J Neural Transm 115:1609–1619

    Article  PubMed  CAS  Google Scholar 

  • Gravius A, Pietraszek M, Dekundy A, Danysz W (2010) Metabotropic glutamate receptors as therapeutic targets for cognitive disorders. Curr Top Med Chem 10:187–206

    Article  PubMed  CAS  Google Scholar 

  • Gregoire L, Ouattara B, Gasparini F, Bilbe G, Johns D, Vranesic I, Sahasramaman S, Gomez-Mancilla B, DiPaolo T (2009) Antidyskinetic effect of AFQ056 a novel metabotropic glutamate receptor type 5 (mGluR5) antagonist in MPTP monkeys. Soc Neurosci Abstr 39:326.15

    Google Scholar 

  • Hill MP, Girard F, Keywood C, Poli S-M, Crossmann AR, Ravenscroft P, Li Q, Bezard E, Mutel V (2010) ADX48621, a novel mGlu5 negative allosteric modulator alleviates l-DOPA-induced chorea and dystonia in the MPTP-lesioned macaque model of Parkinson’s disease. Mov Disord 25(Suppl. 2):S281–S282

    Google Scholar 

  • Hudson LJ, Bevan S, McNair K, Gentry C, Fox A, Kuhn R, Winter J (2002) Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia. J Neurosci 22:2660–2668

    PubMed  CAS  Google Scholar 

  • Johnston TH, Fox SH, McIldowie MJ, Piggott MJ, Brotchie JM (2010) Reduction of l-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Pharmacol Exp Ther 333:865–873

    Article  PubMed  CAS  Google Scholar 

  • Konradi C, Westin JE, Carta M, Eaton ME, Kuter K, Dekundy A, Lundblad M, Cenci MA (2004) Transcriptome analysis in a rat model of l-DOPA-induced dyskinesia. Neurobiol Dis 17:219–236

    Article  PubMed  CAS  Google Scholar 

  • Levandis G, Bazzini E, Armentero MT, Nappi G, Blandini F (2008) Systemic administration of an mGluR5 antagonist, but not unilateral subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinson’s disease. Neurobiol Dis 29:161–168

    Article  PubMed  CAS  Google Scholar 

  • Lorrain DS, Correa L, Anderson J, Varney M (2002) Activation of spinal group I metabotropic glutamate receptors in rats evokes local glutamate release and spontaneous nociceptive behaviors: effects of 2-methyl-6-(phenylethynyl)-pyridine pretreatment. Neurosci Lett 327:198–202

    Article  PubMed  CAS  Google Scholar 

  • Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15:120–132

    Article  PubMed  CAS  Google Scholar 

  • Martindale J, Bland-Ward PA, Chessell IP (2001) Inhibition of C-fibre mediated sensory transmission in the rat following intraplantar formalin. Neurosci Lett 316:33–36

    Article  PubMed  CAS  Google Scholar 

  • McCall WD, Tanner KD, Levine JD (1996) Formalin induces biphasic activity in C-fibers in the rat. Neurosci Lett 208:45–48

    Article  PubMed  CAS  Google Scholar 

  • Mela F, Marti M, Dekundy A, Danysz W, Morari M, Cenci MA (2007) Antagonism of metabotropic glutamate receptor type 5 attenuates l-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson’s disease. J Neurochem 101:483–497

    Article  PubMed  CAS  Google Scholar 

  • Morin N, Gregoire L, Gomez-Mancilla B, Gasparini F, Di PT (2010) Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys. Neuropharmacology 58:981–986

    Article  PubMed  CAS  Google Scholar 

  • Murray F, Kennedy J, Hutson PH, Elliot J, Huscroft I, Mohnen K, Russell MG, Grimwood S (2000) Modulation of [3H]MK-801 binding to NMDA receptors in vivo and in vitro. Eur J Pharmacol 397:263–270

    Article  PubMed  CAS  Google Scholar 

  • Neugebauer V (2001) Peripheral metabotropic glutamate receptors: fight the pain where it hurts. Trends Neurosci 24:550–552

    Article  PubMed  CAS  Google Scholar 

  • Otsuka S, Kobayashi Y (1964) Radioisotopic assay for monoamine oxidase determinations in human plasma. Biochem Pharmacol 13:995–1006

    Article  PubMed  CAS  Google Scholar 

  • Ouattara B, Belkhir S, Morissette M, Dridi M, Samadi P, Gregoire L, Meltzer LT, Di PT (2009a) Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61–8048 in MPTP monkeys with levodopa-induced dyskinesias. J Mol Neurosci 38:128–142

    Article  PubMed  CAS  Google Scholar 

  • Ouattara B, Gregoire L, Morissette M, Gasparini F, Vranesic I, Bilbe G, Johns DR, Rajput A, Hornykiewicz O, Rajput AH, Gomez-Mancilla B, Di PT (2009b) Metabotropic glutamate receptor type 5 in levodopa-induced motor complications. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.07.014

  • Paxinos G, Watson C (1982) Rat Brain in Stereotaxic Coordinates. Academic Press, Sydney

    Google Scholar 

  • Pietraszek M, Sukhanov I, Maciejak P, Szyndler J, Gravius A, Wislowska A, Plaznik A, Bespalov AY, Danysz W (2005) Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats. Eur J Pharmacol 514:25–34

    Article  PubMed  CAS  Google Scholar 

  • Rylander D, Iderberg H, Li Q, Dekundy A, Zhang J, Li H, Baishen R, Danysz W, Bezard E, Cenci MA (2010) A mGluR5 antagonist under clinical development improves l-DOPA-induced dyskinesia in parkinsonian rats and monkeys. Neurobiol Dis 39:352–361

    Article  PubMed  CAS  Google Scholar 

  • Samadi P, Gregoire L, Morissette M, Calon F, Hadj TA, Dridi M, Belanger N, Meltzer LT, Bedard PJ, Di PT (2008) mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys. Neurobiol Aging 29:1040–1051

    Article  PubMed  CAS  Google Scholar 

  • Sevostianova N, Danysz W (2006) Analgesic effects of mGlu1 and mGlu5 receptor antagonists in the rat formalin test. Neuropharmacology 51:623–630

    Article  PubMed  CAS  Google Scholar 

  • Simonyi A, Schachtman TR, Christoffersen GR (2010) Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur J Pharmacol 639:17–25

    Article  PubMed  CAS  Google Scholar 

  • Spooren WP, Gasparini F, Bergmann R, Kuhn R (2000) Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. Eur J Pharmacol 406:403–410

    Article  PubMed  CAS  Google Scholar 

  • Valerio A, Paterlini M, Boifava M, Memo M, Spano P (1997) Metabotropic glutamate receptor mRNA expression in rat spinal cord. Neuroreport 8:2695–2699

    Article  PubMed  CAS  Google Scholar 

  • Vanejevs M, Jatzke C, Renner S, Muller S, Hechenberger M, Bauer T, Klochkova A, Pyatkin I, Kazyulkin D, Aksenova E, Shulepin S, Timonina O, Haasis A, Gutcaits A, Parsons CG, Kauss V, Weil T (2008) Positive and negative modulation of group I metabotropic glutamate receptors. J Med Chem 51:634–647

    Article  PubMed  CAS  Google Scholar 

  • Varty GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, Hodgson RA, Lu SX, Nicolussi E, Pond AJ, Parker EM, Hunter JC, Higgins GA, Reggiani A, Bertorelli R (2005) The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles. Psychopharmacology (Berl) 179:207–217

    Article  CAS  Google Scholar 

  • Verhagen ML, Del DP, van den Munckhof P, Fang J, Mouradian MM, Chase TN (1998) Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 50:1323–1326

    Google Scholar 

  • Walker K, Bowes M, Panesar M, Davis A, Gentry C, Kesingland A, Gasparini F, Spooren W, Stoehr N, Pagano A, Flor PJ, Vranesic I, Lingenhoehl K, Johnson EC, Varney M, Urban L, Kuhn R (2001) Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain. Neuropharmacology 40:1–9

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto N, Soghomonian JJ (2009) Metabotropic glutamate mGluR5 receptor blockade opposes abnormal involuntary movements and the increases in glutamic acid decarboxylase mRNA levels induced by l-DOPA in striatal neurons of 6-hydroxydopamine-lesioned rats. Neuroscience 163:1171–1180

    Article  PubMed  CAS  Google Scholar 

  • Young MR, Fleetwood-Walker SM, Dickinson T, Blackburn-Munro G, Sparrow H, Birch PJ, Bountra C (1997) Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord. Brain Res 777:161–169

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Caroline Barberi, Andrea Baude, Sabine Denk, Ralph Gross, and Daniela Schäfer for their skilful and excellent technical assistance by performing the studies and Dr. Barbara Valastro for sharing selectivity data.

Author information

Authors and Affiliations

  1. In Vivo Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany

    Andrzej Dekundy, Andreas Gravius, Małgorzata Pietraszek, Jens Nagel, Martine van der Elst, Flora Mela & Wojciech Danysz

  2. In Vitro Pharmacology, R+D CNS, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany

    Mirko Hechenberger & Christopher G. Parsons

  3. Rent-a-lab, Aspenhaustr. 25, 72770, Reutlingen, Germany

    Carsten Tober

Authors
  1. Andrzej Dekundy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Gravius
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mirko Hechenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Małgorzata Pietraszek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jens Nagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carsten Tober
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martine van der Elst
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Flora Mela
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher G. Parsons
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wojciech Danysz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrzej Dekundy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dekundy, A., Gravius, A., Hechenberger, M. et al. Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on l-DOPA-induced dyskinesia. J Neural Transm 118, 1703–1716 (2011). https://doi.org/10.1007/s00702-010-0526-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-010-0526-0

Keywords

Search

Navigation