Remote control of movement disorders using a photoactive adenosine A(2A) receptor antagonist
| Autor: | Ernest G. Nolen, Jaume Taura, Lucia Squarcialupi, Jordi Hernando, Francisco Ciruela, Víctor Fernández-Dueñas, Gisela Cabré, Kenneth A. Jacobson, Marc López-Cano |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Locomotor activity Adenosine Light Receptor Adenosine A2A Photopharmacology Parkinson's disease Adenosina Pharmaceutical Science Adenosine A2A receptor Striatum Pharmacology Catalepsy Article 03 medical and health sciences Mice 0302 clinical medicine Malaltia de Parkinson Tremor medicine Animals Humans Receptor Optical Fibers Movement disorder Movement Disorders Chemistry Antagonist Brain Long-term potentiation medicine.disease Adenosine receptor Adenosine A2 Receptor Antagonists Disease Models Animal 030104 developmental biology HEK293 Cells SCH442416 030217 neurology & neurosurgery Locomotion medicine.drug |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | Altres ajuts: Fundació la Marató de TV3 (Grant 20152031) G protein-coupled adenosine receptors are promising therapeutic targets for a wide range of neuropathological conditions, including Parkinson's disease (PD). However, the ubiquity of adenosine receptors and the ultimate lack of selectivity of certain adenosine-based drugs have frequently diminished their therapeutic use. Photopharmacology is a novel approach that allows the spatiotemporal control of receptor function, thus circumventing some of these limitations. Here, we aimed to develop a light-sensitive caged adenosine A receptor (A R) antagonist to photocontrol movement disorders. We synthesized MRS7145 by blocking with coumarin the 5-amino position of the selective A R antagonist SCH442416, which could be photoreleased upon violet light illumination (405 nm). First, the light-dependent pharmacological profile of MRS7145 was determined in A R-expressing cells. Upon photoactivation, MRS7145 precluded A R ligand binding and agonist-induced cAMP accumulation. Next, the ability of MRS7145 to block A R in a light-dependent manner was assessed in vivo. To this end, A R antagonist-mediated locomotor activity potentiation was evaluated in brain (striatum) fiber-optic implanted mice. Upon irradiation (405 nm) of the dorsal striatum, MRS7145 induced significant hyperlocomotion and counteracted haloperidol-induced catalepsy and pilocarpine-induced tremor. Finally, its efficacy in reversing motor impairment was evaluated in a PD animal model, namely the hemiparkinsonian 6-hydroxydopamine (6-OHDA)-lesioned mouse. Photo-activated MRS7145 was able to potentiate the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine (L-DOPA). Overall, MRS7145 is a new light-operated A R antagonist with potential utility to manage movement disorders, including PD. |
| Databáze: | OpenAIRE |
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