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 (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 PAMsexhibited 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3,4-Dihydroxyphenylacetic Acid / metabolism
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Adenosine A2 Receptor Antagonists / blood
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Adenosine A2 Receptor Antagonists / metabolism
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Adenosine A2 Receptor Antagonists / therapeutic use*
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Animals
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Brain / drug effects
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Brain / metabolism
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Brain / pathology
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Brain / physiopathology
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Calcium Signaling / drug effects
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Catalepsy / chemically induced
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Catalepsy / drug therapy
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Corpus Striatum / physiopathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Synergism
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Drug Therapy, Combination
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G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
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Glutamic Acid / pharmacology
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HEK293 Cells
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Haloperidol / pharmacology
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Humans
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Levodopa / metabolism
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Levodopa / therapeutic use*
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Male
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Monoamine Oxidase / metabolism
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Motor Neuron Disease / chemically induced
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Motor Neuron Disease / drug therapy
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Motor Neuron Disease / metabolism
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Motor Neuron Disease / pathology
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Motor Neuron Disease / physiopathology
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Oxidopamine / pharmacology
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Parkinson Disease / drug therapy*
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Picolinic Acids / blood
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Picolinic Acids / metabolism
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Picolinic Acids / pharmacokinetics
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Picolinic Acids / pharmacology
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Picolinic Acids / therapeutic use*
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Protein Binding
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Psychomotor Performance / drug effects
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Pyrimidines / blood
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Pyrimidines / metabolism
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Pyrimidines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Reaction Time / drug effects
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Receptors, G-Protein-Coupled / agonists
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Metabotropic Glutamate / agonists*
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Receptors, Metabotropic Glutamate / genetics
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Receptors, Metabotropic Glutamate / metabolism
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Thallium / metabolism
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Transfection
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Triazoles / blood
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Triazoles / metabolism
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Triazoles / therapeutic use
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Adenosine A2 Receptor Antagonists
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G Protein-Coupled Inwardly-Rectifying Potassium Channels
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N-(3-chlorophenyl)picolinamide
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Picolinic Acids
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Pyrimidines
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Receptors, G-Protein-Coupled
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Receptors, Metabotropic Glutamate
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Triazoles
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3,4-Dihydroxyphenylacetic Acid
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Glutamic Acid
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Levodopa
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Oxidopamine
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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
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Thallium
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Tyrosine 3-Monooxygenase
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Monoamine Oxidase
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Haloperidol
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metabotropic glutamate receptor 4