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（CB）受体亚型1的光致变色配体和作用于CB亚型2的配体，它们可以通过光切换其生物活性。通过引入偶氮苯基团来实现配体被UV光转换的性质，可以应用偶氮苯基团的化学修饰来实现更高的光转换以及在更高波长下的转换。在受体水平上，这种光致变色转换有两种结果：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/或它在不同程度上激活受体。根据配体的不同，受体可以打开或关闭。基于我们先前对两种受体亚型的高选择性配体的工作以及对这些配体在CB 2受体中的结合模式的计算研究，我们开发了第一配体，其在照射后结合更强（“亲和力开启开关”）。对于高级药理学研究，将优化该性质，并通过使用不同类别的化学模板，将开发两种亚型的选择性光致变色配体，其不与人体内源性大麻素系统的其他靶标（例如离子通道）相互作用。该项目的一个特别重点是开发在辐照后改变固有活性（功效）的配体（“功效开关”）。这类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，其中还将进行配体亲和力和功效的表征。通过与Camerino大学（意大利），Aberdeen大学（英国），巴塞罗那大学（西班牙）和Max Delbrück中心柏林的合作，这些化合物将用于更精细和复杂的研究，使用这些分子作为工具化合物来解开GPCR的激活和动力学的基本未知过程。

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.