PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.01200/full |
| _version_ | 1818034927803826176 |
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| author | Fabiana Núñez Fabiana Núñez Jaume Taura Jaume Taura Juan Camacho Marc López-Cano Marc López-Cano Víctor Fernández-Dueñas Víctor Fernández-Dueñas Naomi Castro Julio Castro Francisco Ciruela Francisco Ciruela |
| author_facet | Fabiana Núñez Fabiana Núñez Jaume Taura Jaume Taura Juan Camacho Marc López-Cano Marc López-Cano Víctor Fernández-Dueñas Víctor Fernández-Dueñas Naomi Castro Julio Castro Francisco Ciruela Francisco Ciruela |
| author_sort | Fabiana Núñez |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-12-10T06:46:56Z |
| format | Article |
| id | doaj.art-d6349777c10d487da7f672d3cfcb5143 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T06:46:56Z |
| publishDate | 2018-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d6349777c10d487da7f672d3cfcb51432022-12-22T01:58:39ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-10-01910.3389/fphar.2018.01200412475PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement DisordersFabiana Núñez0Fabiana Núñez1Jaume Taura2Jaume Taura3Juan Camacho4Marc López-Cano5Marc López-Cano6Víctor Fernández-Dueñas7Víctor Fernández-Dueñas8Naomi Castro9Julio Castro10Francisco Ciruela11Francisco Ciruela12Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, SpainInstitut de Neurociències, Universitat de Barcelona, Barcelona, SpainUnitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, SpainInstitut de Neurociències, Universitat de Barcelona, Barcelona, SpainPaloBiofarma S.L., Barcelona, SpainUnitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, SpainInstitut de Neurociències, Universitat de Barcelona, Barcelona, SpainUnitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, SpainInstitut de Neurociències, Universitat de Barcelona, Barcelona, SpainPaloBiofarma S.L., Barcelona, SpainPaloBiofarma S.L., Barcelona, SpainUnitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, SpainInstitut de Neurociències, Universitat de Barcelona, Barcelona, SpainAdenosine 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).https://www.frontiersin.org/article/10.3389/fphar.2018.01200/fullPBF509Parkinson’s diseaseadenosine A2A receptorcatalepsylabel-freetremor |
| spellingShingle | Fabiana Núñez Fabiana Núñez Jaume Taura Jaume Taura Juan Camacho Marc López-Cano Marc López-Cano Víctor Fernández-Dueñas Víctor Fernández-Dueñas Naomi Castro Julio Castro Francisco Ciruela Francisco Ciruela PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders Frontiers in Pharmacology PBF509 Parkinson’s disease adenosine A2A receptor catalepsy label-free tremor |
| title | PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders |
| title_full | PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders |
| title_fullStr | PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders |
| title_full_unstemmed | PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders |
| title_short | PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders |
| title_sort | pbf509 an adenosine a2a receptor antagonist with efficacy in rodent models of movement disorders |
| topic | PBF509 Parkinson’s disease adenosine A2A receptor catalepsy label-free tremor |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.01200/full |
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