The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease

Carrie K. Jones, Michael Bubser, Analisa D. Thompson, Jonathan W. Dickerson, Nathalie Turle-Lorenzo, Marianne Amalric, Anna L. Blobaum, Thomas M. Bridges, Ryan D. Morrison, Satyawan Jadhav, Darren W. Engers, Kimberly Italiano, Jacob Bode, J. Scott Daniels, Craig W. Lindsley, Corey R. Hopkins, P. Jeffrey Conn, Colleen M. Niswender

Research output: Contribution to journalArticle

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Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu 4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a- carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu 4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu 4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu 4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A 2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu 4 PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu 4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A 2A antagonists.

Original languageEnglish (US)
Pages (from-to)404-421
Number of pages18
JournalJournal of Pharmacology and Experimental Therapeutics
Volume340
Issue number2
DOIs
StatePublished - Feb 1 2012

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Adenosine
Parkinson Disease
Rodentia
Oxidopamine
Catalepsy
Forelimb
Haloperidol
Rodent Diseases
Secondary Parkinson Disease
Medial Forebrain Bundle
Purinergic P1 Receptor Antagonists
Antiparkinson Agents
Basal Ganglia
Neurodegenerative Diseases
metabotropic glutamate receptor 4
N-(3-chlorophenyl)picolinamide
2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease. / Jones, Carrie K.; Bubser, Michael; Thompson, Analisa D.; Dickerson, Jonathan W.; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L.; Bridges, Thomas M.; Morrison, Ryan D.; Jadhav, Satyawan; Engers, Darren W.; Italiano, Kimberly; Bode, Jacob; Daniels, J. Scott; Lindsley, Craig W.; Hopkins, Corey R.; Conn, P. Jeffrey; Niswender, Colleen M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 340, No. 2, 01.02.2012, p. 404-421.

Research output: Contribution to journalArticle

Jones, CK, Bubser, M, Thompson, AD, Dickerson, JW, Turle-Lorenzo, N, Amalric, M, Blobaum, AL, Bridges, TM, Morrison, RD, Jadhav, S, Engers, DW, Italiano, K, Bode, J, Daniels, JS, Lindsley, CW, Hopkins, CR, Conn, PJ & Niswender, CM 2012, 'The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease', Journal of Pharmacology and Experimental Therapeutics, vol. 340, no. 2, pp. 404-421. https://doi.org/10.1124/jpet.111.187443
Jones, Carrie K. ; Bubser, Michael ; Thompson, Analisa D. ; Dickerson, Jonathan W. ; Turle-Lorenzo, Nathalie ; Amalric, Marianne ; Blobaum, Anna L. ; Bridges, Thomas M. ; Morrison, Ryan D. ; Jadhav, Satyawan ; Engers, Darren W. ; Italiano, Kimberly ; Bode, Jacob ; Daniels, J. Scott ; Lindsley, Craig W. ; Hopkins, Corey R. ; Conn, P. Jeffrey ; Niswender, Colleen M. / The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 340, No. 2. pp. 404-421.
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abstract = "Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu 4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a- carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu 4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu 4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu 4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A 2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu 4 PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu 4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A 2A antagonists.",
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