Remote control of movement disorders using a photoactive adenosine A 2A receptor antagonist
Taura, Jaume (Universitat de Barcelona. Institut de Neurociències)
Nolen, Ernest G. (Colgate University)
Cabré Segura, Gisela (Universitat Autònoma de Barcelona. Departament de Química)
Hernando Campos, Jordi (Universitat Autònoma de Barcelona. Departament de Química)
Squarcialupi, Lucia (National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases (USA))
López Cano, Marc (Universitat de Barcelona. Institut de Neurociències)
Jacobson, Kenneth A. (National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases (USA))
Fernández-Dueñas, Víctor (Universitat de Barcelona. Institut de Neurociències)
Ciruela, Francisco (Universitat de Barcelona. Institut de Neurociències)

Fecha:	2018
Resumen:	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.
Ayudas:	Agencia Estatal de Investigación SAF2017-87349-R Ministerio de Economía y Competitividad PIE14/00034 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1604 Ministerio de Economía y Competitividad CTQ2015-65439-R
Nota:	Altres ajuts: Fundació la Marató de TV3 (Grant 20152031)
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Movement disorder ; Adenosine A2A receptor ; Photopharmacology ; SCH442416 ; Locomotor activity ; Catalepsy ; Tremor ; Parkinson's disease
Publicado en:	Journal of Controlled Release, Vol. 283 (August 2018) , p. 135-142, ISSN 1873-4995

DOI: 10.1016/j.jconrel.2018.05.033
PMID: 29859955

Postprint 18 p, 826.7 KB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias > Grupo de Electroquímica, Fotoquímica y Reactividad Orgánica (GEFRO)
Artículos > Artículos de investigación
Artículos > Artículos publicados