Photo‐BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor

The field of G protein‐coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, photoswitchable agents. Most of the developed tools have targeted the Rhodopsin‐like family (Class A), the largest family of GPCRs. However, to date, all such Class A photoswitchable ligands were designed to act at the orthosteric binding site of these receptors. Herein, we report the development of the first photoswitchable allosteric modulators of Class A GPCRs, designed to target the M1 muscarinic acetylcholine receptor. The presented benzyl quinolone carboxylic acid (BQCA) derivatives, photo‐BQCisA and photo‐BQCtrAns, exhibit complementary photopharmacological behavior and allow reversible control over the receptor using light as an external stimulus. This makes them valuable tools to further investigate M1 receptor signaling and a proof of concept for photoswitchable allosteric modulators at Class A receptors.