title: 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.
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.
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University, Nashville, TN 37212, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.forename: Analisa D
authors.initials: AD
authors.lastname: Thompson
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Dickerson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Turle-Lorenzo
authors.forename: Marianne
authors.initials: M
authors.lastname: Amalric
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: Satyawan
authors.initials: S
authors.lastname: Jadhav
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Kimberly
authors.initials: K
authors.lastname: Italiano
authors.forename: Jacob
authors.initials: J
authors.lastname: Bode
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D016472:Motor Neuron Disease / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy*; D010848:Picolinic Acids / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding; D011597:Psychomotor Performance / Q000187:drug effects; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013793:Thallium / Q000378:metabolism; D014162:Transfection; D014230:Triazoles / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C571150:N-(3-chlorophenyl)picolinamide; D010848:Picolinic Acids; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; D015102:3,4-Dihydroxyphenylacetic Acid; D018698:Glutamic Acid; D007980:Levodopa; D016627:Oxidopamine; C539997:2-(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; D013793:Thallium; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4
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