Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Frontiers in pharmacology, 2018-10, Vol.9, p.1200-1200

Ort / Verlag

Frontiers Media S.A

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Adenosine A 2A receptor (A 2A R) antagonists have emerged as complementary non-dopaminergic drugs to alleviate Parkinson’s disease (PD) symptomatology. Here, we characterize a novel non-xhantine non-furan A 2A R antagonist, PBF509, as a potential pro-dopaminergic drug for PD management. First, PBF509 was shown to be a highly potent ligand at the human A 2A R, since it antagonized A 2A R agonist-mediated cAMP accumulation and impedance responses with K B values of 72.8 ± 17.4 and 8.2 ± 4.2 nM, respectively. Notably, these results validated our new A 2A R-based label-free assay as a robust and sensitive approach to characterize A 2A R 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 A 2A R antagonist with potential utility for PD treatment, and for some of the side effects associated to the current pharmacotherapy (i.e., dyskinesia).