Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders

Hodgson, Robert A.; Bédard, Paul J.; Varty, Geoffrey B.; Kazdoba, Tatiana M.; Paolo, Thérèse Di; Grzelak, Michael E.; Pond, Annamarie J.; HadjTahar, Abdallah; Bélanger, Nancy; Grégoire, Laurent; Dare, Aurelie; Neustadt, Bernard R.; Stamford, Andrew W.; Hunter, John C.

doi:10.1016/j.expneurol.2010.07.011

Cited by 91 publications

(50 citation statements)

References 34 publications

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“…L-DOPA while eliciting significantly less dyskinesia than L-DOPA alone (Bara-Jimenez et al, 2003;Bibbiani et al, 2003). However, istradefylline slightly exacerbated dyskinesia severity in placebo-controlled studies (Hauser et al, 2008;LeWitt et al, 2008), but another A 2A antagonist, preladenant, significantly increased duration of ontime without troublesome dyskinesia in a phase II study (Hodgson et al, 2010).…”

Section: The Adenosine Systemmentioning

confidence: 94%

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

Huot

Johnston²,

Koprich³

et al. 2013

Pharmacol Rev

293

230

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Section: The Adenosine Systemmentioning

confidence: 94%

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

Huot

Johnston²,

Koprich³

et al. 2013

Pharmacol Rev

293

230

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“…Previous studies have shown that selective A 2A antagonists produce robust antiparkinsonian-like effects in animal models of dopamine depletion, and more recently in clinical trials with patients with PD, when given alone or in combination with L-DOPA (Varty et al, 2008;Hodgson et al, 2010;Pinna et al, 2010;Hauser et al, 2011). In another report, coadministration of a group III mGlu agonist with an A 2A antagonist produced an enhanced reduction of haloperidol-induced catalepsy that was greater in magnitude than that observed with either compound administered alone (Lopez et al, 2008).…”

Section: Vu0364770 Enhances the Efficacy Of The A 2a Antagonist Prelamentioning

confidence: 94%

“…Antagonism of adenosine A 2A receptors, expressed on medium spiny GABAergic neurons that project to the GPe, results in decreased inhibition of the GPe and antiparkinsonian-like effects in animal PD models (Hettinger et al, 2001;Hodgson et al, 2010). In a recent phase II, double-blind clinical trial, positive effects were reported on the motor impairments in patients with Parkinson's disease by using the A 2A receptor antagonist preladenant (Hauser et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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

Jones¹,

Bubser²,

Thompson³

et al. 2011

J Pharmacol Exp Ther

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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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“…Consequently, these drugs have therapeutic potential in diseases of dopaminergic hypofunction such as Parkinson's disease. Indeed, A 2A R antagonists have been effective in a variety of animal models of Parkinson's disease Chen et al 2001 ;Hodgson et al 2010 ;Kanda et al 1998Kanda et al , 2000 . Furthermore, caffeine ameliorates the freezing of gait that occurs in Parkinson's disease patients (Kitagawa et al 2007 ) .…”

Section: Movement Disordersmentioning

confidence: 99%

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

Kovács

Dobolyi

2012

Adenosine

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Nucleosides have a wide range of physiological and pathophysiological roles in the human brain as modulators of a variety of neural functions. For example, adenosine, inosine, guanosine, and uridine participate in the mechanisms underlying memory, cognition, sleep, pain, depression, schizophrenia, epilepsy, Alzheimer's disease, Huntington's disease, and Parkinson's disease. Consequently, increasing attention is now being given to the speci fi c role of nucleosides in physiological and pathological processes in the human brain. Different elements of nucleoside system, including nucleoside concentrations, metabolic enzyme activity, and expression of nucleoside transporters and receptors, may be changed under normal and pathological conditions. The alterations suggest that interlinked elements of the nucleoside system are functioning in a tightly concerted manner.Nucleoside levels, activity of nucleoside metabolic enzymes, and expression of nucleoside transporters and receptors are unevenly distributed in the brain, suggesting that nucleosides have different roles in functionally distinct human brain areas. The aim of this chapter is to summarize our present knowledge of the anatomical distribution of nucleoside system in the human brain, placing emphasis on potential therapeutic pharmacological strategies.

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Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders

Cited by 91 publications

References 34 publications

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

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

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

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