CVN636 potentiates orthosteric agonist responses selectively at mGlu7/7 homodimers

Abstract

The metabotropic glutamate receptor 7 (mGlu7) is an emerging therapeutic target for central nervous system disorders, but progress has been limited by a lack of selective pharmacological tools. CVN636 was recently reported as a potent and selective allosteric agonist of this receptor, capable of receptor activation in the absence of glutamate, with demonstrated efficacy in a rodent model of alcohol use disorder. Here, using complementary bioluminescence resonance energy transfer-based assays that measure both downstream signaling and G protein recruitment, we show that CVN636 does not activate the receptor on its own. Instead, CVN636 acts as a positive allosteric modulator that enhances the potency and efficacy of orthosteric agonist responses, including those of glutamate, in an agonist-dependent manner. Blockade of orthosteric agonist binding with a competitive antagonist abolished CVN636 activity, consistent with this mechanism. Furthermore, using an assay that distinguishes signaling from defined receptor dimers, we find that CVN636 activity is selective for mGlu7/7 homodimers and does not extend to any mGlu7-containing heterodimer tested. Thus, in our assay system CVN636 is an mGlu7/7 homodimer-selective positive allosteric modulator of this receptor, suggesting that its in vivo actions likely stem from action at these homomers.