One- and Two-Photon Excitable Photoswitchable Orthoand Allosteric Ligands of Class A GPCRs
Online Publication Service of Würzburg University (Würzburg University) January 30, 2024 Hubert Georg Lambert Gerwe
Photoswitchable ligands for two class A G protein-coupled receptors (GPCRs) were designed, synthesized, and characterized. For the serotonin 2A receptor (5-HT2AR), a photoswitchable derivative of the psychedelic N,N-dimethyltryptamine (photo-DMT) was created that binds with similar affinities in its cis- and trans-configurations but produces different levels of receptor activation, acting as an efficacy switch. For the muscarinic acetylcholine receptor 1 (M1R), photoswitchable derivatives of the agonist xanomeline, called xanoswitches, were optimized for two-photon near-infrared light activation, enabling bidirectional modulation of neuronal activity in vivo, and for one-photon amber-light activation, allowing control of calcium oscillations and zebrafish motility. The work also presents the first allosteric photoswitch for class A GPCRs, using the M1 positive allosteric modulator BQCA to create Photo-BQCAs that dynamically modulate cooperativity.