Beta-adrenoceptors (ß-AR) are prototypical G protein-coupled receptors (GPCR) and important pharmacological targets for numerous diseases. Indeed, a number of approved drugs target ß-AR, which are key regulators of many physiological functions. Among other examples, ß1-AR antagonists (known as ß-Blockers) are first-line therapies for the treatment of heart failure, and ß2-AR agonists, which act as bronchodilators, are widely used for the treatment of breathing pathologies. Considering the medical relevance of these receptors, achieving a reversible and localized control of their activity would provide a powerful research and clinical tool.
GPCR signaling is currently recognized as a multidimensional process governed by molecular, spatial and temporal components. Uncovering the role of each of these dimensions is crucial to improve our knowledge on cell communication, to understand how different pathways give rise to cellular and physiological effects, and to know how can we interact with biological systems with precision using drugs. Photopharmacology is an emerging field in which light-sensitive molecules are used to control the function of a given target protein in native tissues. The modulation of the target activity is achieved by small, drug-like, photoregulated ligands. By the use of light, both spatial and temporal control of the compound activity can be achieved in unprecedented manners compared to conventional pharmacology. These ligands have the potential to provide highly precise and controllable therapeutic actions that may result in increased efficacies and reduced side effects. Importantly, photopharmacology may allow to gain mechanistic insight on the interplay between the activation time and the receptor location during signaling processes in non-modified cells, tissues and whole organisms.
Our research focused on the generation of new molecular tools for beta-adrenoceptors photopharmacology will be presented in this communication. First, several libraries of light-sensitive compounds with the aim to regulate ß-AR activity with spatiotemporal precision were designed and synthesized. Subsequent testing in cell preparations demonstrated the successful development of compounds with promising pharmacological properties, which can be reversibly and irreversibly controlled by light. Among those, several hit compounds were identified as ligands for beta-1 and beta-2 adrenoceptors with low nanomolar activities. These libraries compounds were found to be active enough to become useful photopharmacological tools, so we also performed in vivo experiments to determine their research potential in physiological environments. Indeed, the discovered molecules enabled a fine control of ß-AR in their native environment. We believe that the results of these studies will certainly open the door to innovative research procedures and may inspire future therapies targeting ß-AR
