Unitat de Farmacologia, Departament Patologia i Terapéutica Experimental, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Institut de Neurociències, Universitat de Barcelona, Spain.
Colgate University, Hamilton, USA.
J Control Release. 2018 Aug 10;283:135-142. doi: 10.1016/j.jconrel.2018.05.033. Epub 2018 May 31.
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.
G 蛋白偶联腺苷受体是治疗多种神经病理学疾病的有前途的治疗靶点，包括帕金森病 (PD)。然而，由于腺苷受体无处不在，以及某些基于腺苷的药物最终缺乏选择性，它们的治疗用途经常受到限制。光药理学是一种新方法，可以实现受体功能的时空控制，从而规避其中的一些限制。在这里，我们旨在开发一种对光敏感的笼状腺苷 A 受体 (AR) 拮抗剂来光控运动障碍。我们通过用香豆素阻断选择性 AR 拮抗剂 SCH442416 的 5-氨基位置来合成 MRS7145，当用紫光（405nm）照射时可以将其光释放。首先，在表达 AR 的细胞中确定了 MRS7145 的光依赖性药理学特征。光激活后，MRS7145 阻止了 AR 配体结合和激动剂诱导的 cAMP 积累。接下来，评估了 MRS7145 以光依赖方式阻断 AR 的能力。为此，评估了 AR 拮抗剂介导的脑（纹状体）光纤植入小鼠的运动活性增强。当照射背侧纹状体（405nm）时，MRS7145 诱导明显的多动，并对抗了氟哌啶醇引起的僵住和毛果芸香碱引起的震颤。最后，在帕金森病动物模型，即半帕金森病 6-羟多巴胺（6-OHDA）损伤的小鼠中，评估了其逆转运动障碍的功效。光激活的 MRS7145 能够增强 L-3,4-二羟基苯丙氨酸（l-DOPA）诱导的对侧旋转次数。总体而言，MRS7145 是一种新的光操作的 AR 拮抗剂，具有治疗运动障碍的潜力，包括 PD。
