Remote control of movement disorders using a photoactive adenosine A2A receptor antagonist

Abstract

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 (AR) antagonist to photocontrol movement disorders. We synthesized MRS7145 by blocking with coumarin the 5-amino position of the selective AR antagonist SCH442416, which could be photoreleased upon violet light illumination (405 nm). First, the light-dependent pharmacological profile of MRS7145 was determined in AR-expressing cells. Upon photoactivation, MRS7145 precluded AR ligand binding and agonist-induced cAMP accumulation. Next, the ability of MRS7145 to block AR in a light-dependent manner was assessed in vivo. To this end, AR 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 AR antagonist with potential utility to manage movement disorders, including PD.

Control of glutamate release by complexes of adenosine and cannabinoid receptors

“…Data manipulations and statistical analyses for all CODA-RET, BRET, and complementation experiments were performed with GraphPad Prism 7.0 software (La Jolla, CA). cAMP accumulation cAMP accumulation was measured using the LANCE Ultra cAMP kit (PerkinElmer, Waltham, MA, USA) as previously described [73]. In brief, HEK-293T cells were seeded in white 384-wells plates in Dulbecco's modified Eagle's medium (DMEM) (Sigma-Aldrich) containing zardaverine (up to 50 μM; Calbiochem, San Diego, CA, USA) and, when using A2AR ligands, adenosine deaminase (ADA, 0.5 U/ml; Roche Diagnostics, GmbH, Mannheim, Germany).…”

Strategies and considerations of G-protein-coupled receptor photopharmacology

“…Since the first demonstration of the suitability of photocaged compounds to modulate biological systems in the late 1970s, a multitude of molecules employing this mechanism of action have emerged and shown promise in preclinical studies (Font et al, 2017;Kaplan, Forbush, & Hoffman, 1978;Taura et al, 2018). For example, techniques incorporating photocaged compounds have found utility in describing the functional connectivity of circuits within the central nervous system.…”

“…Another study has recently shown that the photo-caged A 2A antagonist, MRS7145, shows efficacy in a number of animal models that represent aspects of the symptomology of Parkinson's disease (Taura et al, 2018). Demonstrating the potential efficacy of photocaged A2A antagonists to manage the symptomology of movement disorders including, Parkinson's disease.…”

“…Accordingly, the electronic properties of molecules should be examined in the design process of photoswitchable ligands and the synthesised ligands should be tested against glutathionemediated reduction (Velema et al, 2014). Photoswitchable ligands containing azobenzene cores, nevertheless, have shown in vivo efficacy suggesting that their potential for metabolism may not be a limiting factor (Font et al, 2017;Taura et al, 2018;Zussy et al, 2018) (Mehta et al, 2017;Morstein et al, 2019).…”

“…As previously mentioned, photo-controllable ligands that target mGlu receptors demonstrate analgesic activity both peripherally and centrally in mice, while photoswitchable analogues of Sphingosine-1-phosphate (S1P) can reversibly control S1P3-dependent hypersensitivity to pain of rodents (Font et al, 2017;Morstein et al, 2019;Zussy et al, 2018). The photocaged A 2A adenosine receptor antagonist, MRS7145, was also recently shown to demonstrate efficacy in reversing motor impairment in a preclinical model of Parkinson's disease (Taura et al, 2018). These studies have demonstrated the potential benefit and feasibility of applying photopharmacological approaches in an in vivo setting and may pave the way for opportunities for innovation in light-regulated therapeutics.…”