Remote control of movement disorders using a photoactive adenosine A <inf>2A</inf> receptor antagonist

Jaume Taura, Ernest G. Nolen, Gisela Cabré, Jordi Hernando, Lucia Squarcialupi, Marc López-Cano, Kenneth A. Jacobson, Víctor Fernández-Dueñas, Francisco Ciruela

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

© 2018 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 2A receptor (A 2A R) antagonist to photocontrol movement disorders. We synthesized MRS7145 by blocking with coumarin the 5-amino position of the selective A 2A 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 2A R-expressing cells. Upon photoactivation, MRS7145 precluded A 2A R ligand binding and agonist-induced cAMP accumulation. Next, the ability of MRS7145 to block A 2A R in a light-dependent manner was assessed in vivo. To this end, A 2A 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 2A R antagonist with potential utility to manage movement disorders, including PD.
Original languageEnglish
Pages (from-to)135-142
JournalJournal of Controlled Release
Volume283
DOIs
Publication statusPublished - 10 Aug 2018

Keywords

  • Adenosine A receptor 2A
  • Catalepsy
  • Locomotor activity
  • Movement disorder
  • Parkinson's disease
  • Photopharmacology
  • SCH442416
  • Tremor

Fingerprint

Dive into the research topics of 'Remote control of movement disorders using a photoactive adenosine A <inf>2A</inf> receptor antagonist'. Together they form a unique fingerprint.

Cite this