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

Autor: Colleen M. Niswender, Jacob Bode, Corey R. Hopkins, Satyawan Jadhav, Ryan D. Morrison, Nathalie Turle-Lorenzo, J. Scott Daniels, Kimberly Italiano, P. Jeffrey Conn, Carrie K. Jones, Marianne Amalric, Anna L. Blobaum, Thomas M. Bridges, Darren W. Engers, Jonathan W. Dickerson, Michael Bubser, Craig W. Lindsley, Analisa D. Thompson
Přispěvatelé: Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2011
Předmět:
Male
Striatum
Pharmacology
Receptors
Metabotropic Glutamate
Receptors
G-Protein-Coupled
Levodopa
Rats
Sprague-Dawley
chemistry.chemical_compound
[SCCO]Cognitive science
0302 clinical medicine
Thallium
Picolinic Acids
ComputingMilieux_MISCELLANEOUS
0303 health sciences
Chemistry
Metabotropic glutamate receptor 4
Brain
Drug Synergism
Parkinson Disease
Receptor antagonist
3. Good health
Adenosine A2 Receptor Antagonists
Substantia Nigra
Molecular Medicine
Drug Therapy
Combination
Protein Binding
Allosteric modulator
Tyrosine 3-Monooxygenase
medicine.drug_class
Glutamic Acid
Substantia nigra
Catalepsy
Transfection
03 medical and health sciences
Drug Discovery and Translational Medicine
Preladenant
medicine
Reaction Time
Animals
Humans
Calcium Signaling
Motor Neuron Disease
Rats
Wistar
Oxidopamine
Monoamine Oxidase
030304 developmental biology
Dose-Response Relationship
Drug
[SCCO.NEUR]Cognitive science/Neuroscience
Antagonist
Triazoles
medicine.disease
Corpus Striatum
Rats
Disease Models
Animal
HEK293 Cells
Pyrimidines
G Protein-Coupled Inwardly-Rectifying Potassium Channels
3
4-Dihydroxyphenylacetic Acid
Haloperidol
030217 neurology & neurosurgery
Psychomotor Performance
Zdroj: Journal of Pharmacology and Experimental Therapeutics
Journal of Pharmacology and Experimental Therapeutics, American Society for Pharmacology and Experimental Therapeutics, 2012, 340 (2), pp.404-421. ⟨10.1124/jpet.111.187443⟩
Journal of Pharmacology and Experimental Therapeutics, 2012, 340 (2), pp.404-421. ⟨10.1124/jpet.111.187443⟩
ISSN: 1521-0103
0022-3565
DOI: 10.1124/jpet.111.187443⟩
Popis: 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 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 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 mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 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 (A2A) 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 mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists.
Databáze: OpenAIRE
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