A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy.
The investigation of the mode and time course of the activation of G-protein-coupled receptors (GPCRs), in particular muscarinic acetylcholine (mACh or M) receptors, is still in its infancy despite the tremendous therapeutic relevance of M receptors and GPCRs in general. We herein made use of a dualsteric ligand that can concomitantly interact with the orthosteric, that is, the neurotransmitter, binding site and an allosteric one. We synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M1 receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated by light. We also applied BQCCAI to investigate the time course of several receptor activation processes.
['Agnetta|Luca|L|0000-0002-1033-3197', 'Kauk|Michael|M|', 'Canizal|Maria Consuelo Alonso|MCA|', 'Messerer|Regina|R|', 'Holzgrabe|Ulrike|U|0000-0002-0364-7278', 'Hoffmann|Carsten|C|', 'Decker|Michael|M|0000-0002-6773-6245']
D001665:Binding Sites D031541:Fluorescence Resonance Energy Transfer D006801:Humans D008024:Ligands D018377:Neurotransmitter Agents D010777:Photochemistry D043562:Receptors, G-Protein-Coupled D011976:Receptors, Muscarinic
dualsteric ligands G-protein-coupled receptors azobenzenes acetylcholine receptors photopharmacology