Caged-carvedilol as a new tool for visible-light photopharmacology of β-adrenoceptors in native tissues

Adrenoceptors are G protein-coupled receptors involved in a large variety of physiological processes, also under pathological conditions. This is due in large part to their ubiquitous expression in the body exerting numerous essential functions. Therefore, the possibility to control their activity with high spatial and temporal precision would constitute a valuable research tool. In this study, we present a caged version of the approved non-selective β-adrenoceptor antagonist carvedilol, synthesized by alkylation of its secondary amine with a coumarin derivative. Introducing this photo-removable group abolished carvedilol physiological effects in cell cultures, mouse isolated perfused hearts and living zebrafish larvae. Only after visible light application, carvedilol was released and the different physiological systems were pharmacologically modulated in a similar manner as the control drug. This research provides a new photopharmacological tool for a wide range of research applications that may help in the development of future precise therapies.We thank Maria José Bleda (IQAC-CSIC, Barcelona), Ignacio Pérez (IQAC-CSIC, Barcelona), Yolanda Pérez (IQAC-CSIC, Barcelona) and Carme Serra (SimChemSiMChem, IQAC-CSIC, Barcelona) for technical support. We thank Dr. Kees Jalink (The Netherlands Cancer Institute, Amsterdam, the Netherlands) for providing the plasmids encoding for the Epac-SH188 biosensor. We thank the University of Vic-Central University of Catalonia (UVic-UCC), Dr. Malu Calle and Dr. Marta Otero for the material assignment which helped in some biological assays. This work was supported by ERDF-FEDER European Fund (projects CTQ2017-89222-R) and by the Catalan government (2017SGR 1604) to AL. Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (PID2020-120499RB-I00) supported XR and AL. XR research was financed by the Spanish Ministry of Economy, Industry and Competitiveness (SAF2015-74132-JIN). MF was supported by the “Agencia Estatal deInvestigación” from the Spanish Ministry of Science and Innovation and the IDAEA-CSIC, a Centre of Excellence Severo Ochoa (CEX2018-000794-S). ARS has a consolidated Miguel Servet contract and was financed by by the Catalan government (2017-SGR-1807). ADC received the support of a fellowship from “la Caixa” Foundation (ID 100010434) under the fellowship codeLCF/BQ/DE18/11670012.Peer reviewe