A new ethyladenine antagonist of adenosine A2A receptors: Behavioral and biochemical characterization as an antiparkinsonian drug

Pinna, Annalisa; Tronci, Elisabetta; Schintu, Nicoletta; Simola, Nicola; Volpini, Rosaria; Pontis, Silvia; Cristalli, Gloria; Morelli, Micaela

doi:10.1016/j.neuropharm.2009.11.012

Cited by 42 publications

(62 citation statements)

References 47 publications

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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%

“…Previous preclinical and clinical studies have demonstrated that A 2A antagonists produce robust antiparkinsonian effects 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). Lopez et al (2008) reported that coadministration of the group III mGlu agonist (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic Fig.…”

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confidence: 99%

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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

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

confidence: 94%

mentioning

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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“…How do motor strategies differ according to the task undertaken by the animal (e.g., discrimination of object shape, size, position, texture) (Ganguly and Kleinfeld 2004)? Are head and whisker motion-sensitive markers for nervous system dysfunction in animal models of substance abuse (Medina and Krahe 2008) or pathology such as Parkinson's disease (Pinna et al 2010)?…”

Section: Discussionmentioning

confidence: 99%

Unsupervised quantification of whisking and head movement in freely moving rodents

Perkon

Košir

Itskov

et al. 2011

Journal of Neurophysiology

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“…Specifically, acute administration of several adenosine A 2A receptor antagonists induced no contralateral rotations per se, but significantly potentiated rotational behaviour induced by L-DOPA or apomorphine and by either dopamine D 1 or D 2 receptor agonists, in hemiparkinsonian rodents (Table 7. 1;Fenu et al 1997;Hodgson et al 2009;Koga et al 2000;Pinna et al 1996Pinna et al , 2005Pinna et al , 2010Pollack and Fink 1996;Rose et al 2007;Tronci et al 2007;Vellucci et al 1993;Weiss et al 2003). Furthermore, in hemiparkinsonian rats, more sophisticated measurements of akinesia, bradykinesia, and gait impairment have been assessed.…”

Section: Effect Of a 2a Receptor Antagonists On Akinesia Bradykinesimentioning

confidence: 99%

“…Indeed, hemiparkinsonian rats made less steps with the forelimb contralateral to the lesion, compared with their ipsilateral forelimb, showing a marked reduction of movements defined as hypokinesia (Chang et al 1999;Olsson et al 1995;Pinna et al 2007Pinna et al , 2010. Moreover, hemiparkinsonian rats show marked and long-lasting impairment in the initiation time of stepping movement of the contralateral to the lesioned side, an impairment considered to be of symptomatic validity for the initiation of movement deficit present in parkinsonian patients (Meredith and Kang 2006;Olsson et al 1995;Pinna et al 2007Pinna et al , 2010. Both deficits described were effectively counteracted by a dose of L-DOPA at sub-threshold levels for induction of rotation.…”

Section: Effect Of a 2a Receptor Antagonists On Akinesia Bradykinesimentioning

confidence: 99%

Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

Pinna

2015

Current Topics in Neurotoxicity

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Parkinson's disease (PD) is primarily a neurological basal ganglia (BG)-related disorder caused by progressive degeneration of the nigrostriatal dopaminergic neurons, which results in the cardinal motor symptoms of PD, including bradykinesia (slow movement and difficulty in initiation movement), resting tremor, muscle tone rigidity, postural instability, and sensorimotor integration deficits. The gold standard of PD therapy is characterized by the dopamine precursor L-DOPA however, after several years, this therapy leads to neuropsychiatric and motor complications, including fluctuations in motor response and dyskinesias, which develop in the majority of patients. Consequently, one of the main targets of research in PD is to identify alternative therapeutic approaches to ameliorate PD symptoms without inducing motor complications. Among the non-dopaminergic strategies for PD, one of the most promising is represented by adenosine A 2A receptor antagonists, due to the colocalization of these receptors and dopamine D 2 receptors in the striatopallidal neurons of the BG, which provides the anatomical basis for the existence of a functional antagonistic interaction between these receptors. Thus, extensive preclinical studies have been performed to prove the effectiveness of adenosine A 2A receptor blockade in counteracting the cardinal motor symptoms of PD.This chapter describes the effects of A 2A antagonists alone or in combination with L-DOPA against the cardinal motor symptoms of PD, using rodent and primate models of PD, and the main mechanisms responsible for these anti-parkinsonian effects. In addition, findings suggesting the potential utilization of A 2A antagonists, as adjunctive treatments to L-DOPA to reduce the L-DOPA induced wearing-off without modifying dyskinetic movements, have been reviewed. Keywords Parkinson's disease · Rodent models · Non-human primate models · Catalepsy · Rigidity · Tremor · 6-Hydroxydopamine lesion · MPTP lesion · A 2A receptor antagonists · Adenosine

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A new ethyladenine antagonist of adenosine A2A receptors: Behavioral and biochemical characterization as an antiparkinsonian drug

Cited by 42 publications

References 47 publications

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

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

Unsupervised quantification of whisking and head movement in freely moving rodents

Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

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