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

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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.