Discovery of CVN636 : A Highly Potent, Selective, and CNS Penetrant mGluR 7 Allosteric Agonist.
Louise DicksonMartin TeallElodie ChevalierToni CheungGemma M LiwickiStephen MackAnne StephensonKathryn WhiteRichard FosbearyDavid C HarrisonNicola L BriceKevin DoyleRoberto CiccocioppoChaobo WuSarah AlmondToshal R PatelPhilip MitchellMatt BarnesAndrew P AyscoughLee A DawsonMark CarltonRoland W BürliPublished in: ACS medicinal chemistry letters (2023)
The low affinity metabotropic glutamate receptor mGluR 7 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 mGluR 7 agonists. Of particular interest is the chromane CVN636 , a potent (EC 50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR 7 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 mGluR 7 and glutamatergic dysfunction.