Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

Journal of Medicinal Chemistry
Julie L EngersKyle A Emmitte

Abstract

Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

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Citations

Jul 14, 2016·Expert Opinion on Drug Discovery·Agnieszka Pałucha-Poniewiera, Andrzej Pilc
Oct 12, 2017·The International Journal of Neuropsychopharmacology·Yoshiaki MiyamotoAtsumi Nitta
Jul 1, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Adam G WalkerP Jeffrey Conn
Feb 26, 2019·Expert Opinion on Therapeutic Targets·Roberta CelliFerdinando Nicoletti
Oct 30, 2019·Current Topics in Medicinal Chemistry·Junliang Hao, Qi Chen
Sep 24, 2020·Expert Opinion on Drug Discovery·Laura Musazzi
Mar 22, 2019·Molecular Psychiatry·Ronald S DumanBrendan Hare
Oct 26, 2018·Frontiers in Molecular Neuroscience·Mariacristina MazzitelliVolker Neugebauer
Apr 3, 2019·Chronic Stress·Shigeyuki ChakiKenichi Fukumoto
Mar 16, 2021·Expert Opinion on Therapeutic Patents·Alshaima'a M Qunies, Kyle A Emmitte
May 27, 2021·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Max E JoffeP Jeffrey Conn
Sep 28, 2017·ACS Medicinal Chemistry Letters·Katrina A BollingerCraig W Lindsley
Sep 28, 2017·ACS Medicinal Chemistry Letters·Julie L EngersCraig W Lindsley

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