A photoswitchable positive allosteric modulator to control the activation of the metabotropic glutamate receptor 5 by light

1. The metabotropic glutamate receptor 5 (mGlu 5 ) is widely expressed in the brain, where it plays an important role in synaptic plasticity, learning and memory, making it a therapeutic target of interest in various neurological disorders. In this study, we developed a photoswitchable positive allosteric modulator (PAM) of the mGlu 5 , as a novel tool for this clinically relevant drug target. To that aim, we used an azologisation strategy of the mGlu 5 PAM agonist VU0424465 leading to the molecule azoglurax. We observed a reversible photoisomerization of azoglurax in solution with optimal wavelengths of 365 nm and 435 nm for trans to cis and cis to trans isomerization, respectively. In cell-based assays, azoglurax potentiates the agonist-induced activity of mGlu 5 with a sub-micromolar potency in the dark. This potency is reduced under UV illumination. Similar to its parent molecule, azoglurax acts as an allosteric agonist of mGlu 5 , activating the receptor in absence of glutamate, as demonstrated on a glutamate-insensitive mutant receptor. Docking and site-directed mutagenesis experiments also suggest that azoglurax and VU0424465 bind the same pocket. In addition, molecular dynamics on cis -azoglurax-bound mGlu 5 suggests that it azoglurax cis isomer does not bind stably in the receptor, in contrast to the trans -isomer, explaining the difference of activity between the two isomers. In conclusion, azoglurax is the first mGlu 5 photoswitchable PAM agonist reported to date, retaining the properties and the binding mode of its parent in the dark, while the insertion of an azobenzene confers light-regulated activity. Graphical abstract