Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist

• DOI: 10.1021/jacs.9b03505
• Publication Date: 2019-04-22T15:21:59Z
• Authors: Fabio Riefolo; Carlo Matera; Aida Garrido-Charles; Alexandre M. J. G...; Rosalba Sortino; Luca Agnetta; Enrique Claro; Roser Masgrau; Ulrike Holzgrabe; Montserrat Batlle; Michael Decker; Eduard Guasch; Pau Gorostiza
• Keywords: Sympathetic Nervous System; Infrared Rays; Xenopus; Muscarinic Agonists; Structure-Activity Relationship; 03 medical and health sciences; Heart Rate; Parasympathetic Nervous System; Animals; Rats, Wistar; Ones electromagnètiques; Receptor, Muscarinic M2; 0303 health sciences; Electromagnetic waves; Dose-Response Relationship, Drug; Molecular Structure; Calci; Stereoisomerism; Photochemical Processes; Rats; 3. Good health; Molecular Docking Simulation; Calcium; Animals; Dose-Response Relationship, Drug; Heart Rate; Infrared Rays; Molecular Docking Simulation; Molecular Structure; Muscarinic Agonists; Parasympathetic Nervous System; Photochemical Processes; Rats; Rats, Wistar; Receptor, Muscarinic M2; Stereoisomerism; Structure-Activity Relationship; Sympathetic Nervous System; Xenopus

Light-triggered reversible modulation of physiological functions offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. To validate the method, we show that PAI photoisomers display different cardiac effects in a mammalian animal model, and demonstrate reversible, real-time photocontrol of cardiac function in translucent wildtype tadpoles. PAI can also effectively activate M2 receptors using two-photon excitation with near-infrared light, which overcomes the scattering and low penetration of short-wavelength illumination, and offers new opportunities for intravital imaging and control of cardiac function.