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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 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
J Pharmacol Exp Ther. 2012 340 (2): 404-21

PMID: 22088953 · PMCID: PMC3263969 · DOI:10.1124/jpet.111.187443

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.

MeSH Terms (37)

3,4-Dihydroxyphenylacetic Acid Adenosine A2 Receptor Antagonists Animals Brain Calcium Signaling Catalepsy Corpus Striatum Disease Models, Animal Dose-Response Relationship, Drug Drug Synergism Drug Therapy, Combination Glutamic Acid G Protein-Coupled Inwardly-Rectifying Potassium Channels Haloperidol HEK293 Cells Humans Levodopa Male Monoamine Oxidase Motor Neuron Disease Oxidopamine Parkinson Disease Picolinic Acids Protein Binding Psychomotor Performance Pyrimidines Rats Rats, Sprague-Dawley Rats, Wistar Reaction Time Receptors, G-Protein-Coupled Receptors, Metabotropic Glutamate Substantia Nigra Thallium Transfection Triazoles Tyrosine 3-Monooxygenase

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