<i>h</i>M1 muscarinic acetylcholine receptors are key actuators in learning and memory processes and may hold therapeutic potential in the treatment of cognitive impairments such as schizophrenia and Alzheimer’s disease. Dualsteric ligands of G protein-coupled receptors are known to be highly selective as they interact with both orthosteric and allosteric binding sites of the receptor. The modification of the spacer length between the orthosteric and allosteric moieties of the iperoxo (orthosteric agonist)/BQCAd-type (positive allosteric modulator) hybrids controls the efficacy and leads to different degrees of partial agonism. A molecular photoswitchable azobenzene moiety has been incorporated as a linker between the agonist and the positive allosteric modulator, giving rise to a photoresponsive BQCA-azobenzene-iperoxo (BQCAAI) hybrid compound and the photochromic behaviour has been studied in detail. FRET studies were conducted and the extent of G<sub>q</sub> activation measured to test and quantify the mode and extent of receptor activation of this first photoswitchable dualsteric M1 ligand. The ligand allows the change between an inactive purely allosteric and the active orthosteric/allosteric binding pose in a light-controlled fashion and offers the possibility to study the process of receptor activation at the molecular level with high temporal resolution.

Photoswitchable dualsteric M1 ligand

253rd National Meeting (2017)

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