PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders.

Fabiana Núñez,Julio Castro,Naomi Castro,Jaume Taura,Marc López-Cano,Francisco Ciruela,Víctor Fernández-Dueñas,Juan Camacho

doi:10.3389/fphar.2018.01200

Abstract

Adenosine A2A receptor (A2AR) antagonists have emerged as complementary non-dopaminergic drugs to alleviate Parkinson’s disease (PD) symptomatology. Here, we characterize a novel non-xhantine non-furan A2AR antagonist, PBF509, as a potential pro-dopaminergic drug for PD management. First, PBF509 was shown to be a highly potent ligand at the human A2AR, since it antagonized A2AR agonist-mediated cAMP accumulation and impedance responses with KB values of 72.8 ± 17.4 and 8.2 ± 4.2 nM, respectively. Notably, these results validated our new A2AR-based label-free assay as a robust and sensitive approach to characterize A2AR ligands. Next, we evaluated the efficacy of PBF509 reversing motor impairments in several rat models of movement disorders, including catalepsy, tremor, and hemiparkinsonism. Thus, PBF509 (orally) antagonized haloperidol-mediated catalepsy, reduced pilocarpine-induced tremulous jaw movements and potentiated the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in unilaterally 6-OHDA-lesioned rats. Moreover, PBF509 (3 mg/kg) inhibited L-DOPA-induced dyskinesia (LID), showing not only its efficacy on reversing parkinsonian motor impairments but also acting as antidyskinetic agent. Overall, here we describe a new orally selective A2AR antagonist with potential utility for PD treatment, and for some of the side effects associated to the current pharmacotherapy (i.e., dyskinesia).

Highlights

Parkinson’s disease (PD) is a neurodegenerative condition affecting around 1% of the population over the age of 65 (Meissner et al, 2011)
The affinity of PBF509 for all four human adenosine receptors was recently reported by means of classical radioligand competition binding assays using membrane extracts from cells expressing A1R, A2A receptor (A2AR), A2BR, and A3R (MediavillaVarela et al, 2017)
While the PBF509 KB value was significantly different [F(1,60) = 11.5, P < 0.005] from the one found for a well characterized A2AR antagonist (Todde et al, 2000), SCH442416 (KB = 28.8 ± 7.2 nM; Figure 1), it was within the same range as previously described (Mediavilla-Varela et al, 2017)

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative condition affecting around 1% of the population over the age of 65 (Meissner et al, 2011). PD is characterized by bradykinesia, tremor, and rigidity, which are secondary to the loss of dopamine neurons in the substantia nigra (Poewe and Mahlknecht, 2009). The main therapeutic approach consists of administrating L-3,4dihydroxyphenylalanine (L-DOPA) or dopamine receptor agonists, recovering the functioning of dopaminergic transmission (Poewe, 2009). A number of adverse effects appear upon the long consumption of dopamine-like based drugs (Huot et al, 2013). Dyskinesia is the most reported one, since, in most cases, it critically impedes the normal life of patients. Rotation of dopamine-like based drugs is a normal strategy to diminish the appearance of these secondary effects, but it seems clear that there is a need in PD clinics for searching novel agents that may improve the management of the pathology (Schapira et al, 2006)

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Conclusion