Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR₇ Allosteric Agonist

The low affinity metabotropic glutamate receptor mGluR₇ has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR₇ agonists. Of particular interest is the chromane CVN636, a potent (EC₅₀ 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR₇ compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR₇ and glutamatergic dysfunction.