Development of Photochromic Cannabinoid Receptor Ligands to Investigate G Protein-coupled Receptor Activation and Function

该研究项目的目标是开发作用于大麻素受体亚型1的光致变色配体和作用于大麻素受体亚型2的配体，这些配体的生物活性可以通过光来切换。紫外光开关配体的性质是通过引入偶氮苯基团来实现的，对偶氮苯基团进行化学修饰可以实现更高的光转化率以及在更高波长下的开关。在受体水平上，这种光致变色转换有两个后果：照射后可逆形成的光异构体在受体上显示出不同的亲和力和/或它(或)在不同程度上(使受体失活)。根据配基的不同，受体可以被打开或关闭。基于我们以前对这两种受体亚型的高选择性配体的工作以及对这些配体在CB2受体中的结合模式的计算研究，我们开发了第一种配体，这种配体在辐射后结合更强(“亲和力开关”)。对于高级药理学研究，这一特性将得到优化，通过使用不同类别的化学模板，将开发出两种亚型的选择性光致变色配体，这些配体也不与人体内大麻素系统的其他靶点，如离子通道相互作用。该项目的一个特别重点是开发在辐射后改变固有活性(效率)的配体(“效率开关”)。这些化合物对于研究受体激活和随后的信号级联的模式和时间过程特别相关。这些目标将通过计算和药物化学研究小组的合作来实现，其中还将对配体的亲和力和有效性进行表征。通过与来自意大利卡梅里诺大学(意大利)、阿伯丁大学(英国)、巴塞罗那大学(西班牙)和柏林麦克斯·德尔布吕克中心的研究小组的合作，这些化合物将被应用于更复杂的研究，将这些分子作为工具化合物来揭开GPCRs的激活和动力学这一鲜为人知的过程。

Goal of this research project is the development of photochromic ligands acting at the cannabinoid (CB) receptor subtype 1 and of ligands acting at the CB subtype 2, which can be switched in their biological activity by light. The property of a ligand to be switched by UV light is achieved by incorporation of an azobenzene group, chemical modification of which can be applied to achieve higher photoconversion as well as switching at higher wavelengths. At the receptor level there are two consequences of such photochromic switching: the photoisomer reversibly formed after irradiation shows a different affinity at the receptor and/or it (de)activates the receptor to a different degree. Depending on the Ligand, the receptors can either be switched on or off. Based on our previous work on highly selective ligands for both receptor subtypes and on computational investigations into the binding modes of these ligands in the CB2 Receptor, we have developed first ligands, that bind stronger after irradiation (“affinity-on switches”). For advanced pharmacological studies this property will be optimized and by using different classes of chemical templates, selective photochromic ligands for both subtypes will be developed that do not interact with other targets of the endocannabinoid system of the human body, such as ion channels, either. A special focus of the project is the development of ligands that change intrinsic activity (efficacy) upon irradiation (“efficacy switches”). Such compounds are of particular relevance for investigations into the modes and temporal processes of receptor activation and subsequent signaling cascades. These aims will be achieved by collaboration of computational and medicinal chemical research groups where also characterization of the ligands with regard to affinity and efficacy will take place. By collaboration with groups from the Universities of Camerino (Italy), Aberdeen (UK), Barcelona (Spain) and the Max Delbrück Center Berlin, the compounds will be applied for more elaborate and complex studies, to use these molecular as tool compounds to unravel the largely unknown processes of activation and dynamics of GPCRs.