Characterization of the Potent and Highly Selective A2AReceptor Antagonists Preladenant and SCH 412348 [7-[2-[4-2,4-Difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in Rodent Models of Movement Disorders and Depression

Hodgson, Robert A.; Bertorelli, Rosalia; Varty, Geoffrey B.; Lachowicz, Jean E.; Forlani, Angelo; Fredduzzi, Silva; Cohen-Williams, Mary; Higgins, Guy A.; Impagnatiello, Francesco; Nicolussi, Elisa; Parra, Leonard E.; Foster, Carolyn; Zhai, Ying; Neustadt, B.; Stamford, Andrew W.; Parker, Eric M.; Reggiani, Angelo; Hunter, John C.

doi:10.1124/jpet.108.149617

Cited by 139 publications

(81 citation statements)

References 39 publications

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“…The obtained result for the non-xanthine antagonist preladenant [46] (compound 18 in Fig. 2) in complex with the A 2A receptor is virtually the same as that of ZM241385, where the bicyclic and tricyclic moieties of these two ligands reside in a similar position.…”

Section: Docking Of Antagonistssupporting

confidence: 67%

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Sherbiny

Schiedel²,

Maaß

et al. 2009

J Comput Aided Mol Des

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A three-dimensional model of the human adenosine A2B receptor was generated by means of homology modelling, using the crystal structures of bovine rhodopsin, the beta2-adrenergic receptor, and the human adenosine A2A receptor as templates. In order to compare the three resulting models, the binding modes of the adenosine A2B receptor antagonists theophylline, ZM241385, MRS1706, and PSB601 were investigated. The A2A-based model was much better able to stabilize the ligands in the binding site than the other models reflecting the high degree of similarity between A2A and A2B receptors: while the A2B receptor shares about 21% of the residues with rhodopsin, and 31% with the beta2-adrenergic receptor, it is 56% identical to the adenosine A2A receptor. The A2A-based model was used for further studies. The model included the transmembrane domains, the extracellular and the intracellular hydrophilic loops as well as the terminal domains. In order to validate the usefulness of this model, a docking analysis of several selective and nonselective agonists and antagonists was carried out including a study of binding affinities and selectivities of these ligands with respect to the adenosine A2A and A2B receptors. A common binding site is proposed for antagonists and agonists based on homology modelling combined with site-directed mutagenesis and a comparison between experimental and calculated affinity data. The new, validated A2B receptor model may serve as a basis for developing more potent and selective drugs.

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Section: Docking Of Antagonistssupporting

confidence: 67%

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Sherbiny

Schiedel²,

Maaß

et al. 2009

J Comput Aided Mol Des

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“…Adenosine A 2A -receptor antagonists inhibit motor deficits induced by dopamine antagonists, such as catalepsy and suppressed locomotion [47,48,53,54,55,56,57]. Consistently, adenosine A 2A -receptor antagonists inhibited the motor disability induced by dopaminergic neurotoxins (i.e.…”

Section: Motor Circuitry Of the Basal Gangliamentioning

confidence: 70%

Adenosine A2A-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

Kulisevsky

Poyurovsky

2011

Eur Neurol

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Parkinson’s disease and drug-induced movement disorders (DIMDs) have commonalities in etiology based on impaired dopamine-based neurotransmission. Adenosine A_2A-receptor antagonism may provide a new mechanism through which these disorders can be managed. In the motor circuit, tonic output from the globus pallidus and substantia nigra regulates movement via opposing excitatory and inhibitory inputs to the cerebral cortex through the direct and indirect pathways. Increased activity of the direct pathway increases movement via an inhibitory effect on thalamocortical projection neurons; increased activity of the indirect pathway has the opposite effect. Regulation of these pathways is mediated primarily by reciprocal inhibitory interactions between dopamine and adenosine receptors on neurons of these pathways. Adenosine A_2A receptors are colocalized with dopamine D₂ receptors on the indirect pathway neurons, with A_2A activation opposing the effect of D₂ activation. The A_2A receptors’ role in the pathophysiology of Parkinson’s disease and DIMDs is evidenced by the upregulation of A_2A receptors in patients with Parkinson’s disease and patients receiving long-term administration of dopamine blockers. Further, A_2A-receptor antagonists are effective in reversing parkinsonian motor deficits and extrapyramidal symptoms in animal models of Parkinson’s disease and DIMDs. Understanding the role of A_2A-receptor antagonism in the pathophysiology of Parkinson’s disease and DIMD has therapeutic implications.

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“…Summarizing the main findings concerning dyskinesia, it has been demonstrated that A 2A receptor antagonists, when administered alone, did not induce dyskinesia in both rodents and primates previously rendered dyskinetic by chronic L-DOPA (Grondin et al 1999;Hodgson et al 2010;Jones et al 2013;Kanda et al 1998;Lundblad et al 2002). Moreover, in hemiparkinsonian rats, long-term treatment with a combination of an A 2A receptor antagonist and low doses of L-DOPA induced a stable response in both rotational behaviour and AIMs, suggesting that this association between the two drugs represents a treatment with a low dyskinetic potential (Hodgson et al 2009;Pinna et al 2001;Tronci et al 2007). Conversely, blockade of the adenosine A 2A receptors did not produce any effect on the severity of the AIMs induced by repeated L-DOPA at full dose, when the two drugs were chronically co-administered in hemiparkinsonian rats (Jones et al 2013;Lundblad et al 2003).…”

Section: Effects Of a 2a Receptor Antagonists On L-dopa Induced Dyskimentioning

confidence: 94%

“…7.2) (Drabczyńska et al 2011;Gillespie et al 2009;Hodgson et al 2009;Jones et al 2013;Kanda et al 1994;Mandhane et al 1997;Pinna et al 2005;Shiozaki et al 1999;Shook et al 2010Shook et al , 2013Stasi et al 2006;Villanueva-Toledo 2003;Wardas et al 2003;Weiss et al 2003). Furthermore, the co-administration of several A.…”

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

confidence: 95%

“…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%

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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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Characterization of the Potent and Highly Selective A_2AReceptor Antagonists Preladenant and SCH 412348 [7-[2-[4-2,4-Difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in Rodent Models of Movement Disorders and Depression

Cited by 139 publications

References 39 publications

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Adenosine A<sub>2A</sub>-Receptor Antagonism and Pathophysiology of Parkinson’s Disease and Drug-Induced Movement Disorders

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

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