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

Abstract

1.The metabotropic glutamate receptor 5 (mGlu5) 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 mGlu5, as a novel tool for this clinically relevant drug target. To that aim, we used an azologisation strategy of the mGlu5 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 mGlu5 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 mGlu5, 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 mGlu5 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 mGlu5 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/629646v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1e0c1f4org.highwire.dtl.DTLVardef@dd7e36org.highwire.dtl.DTLVardef@1892657org.highwire.dtl.DTLVardef@1343743_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG