Computationally Guided Identification of Allosteric Agonists of the Metabotropic Glutamate 7 Receptor

Jose María Cid, Hilde Lavreysen, Gary Tresadern, Laura Pérez-Benito, Fulgencio Tovar, Alberto Fontana, Andrés A. Trabanco

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    Abstract

    © 2018 American Chemical Society. The metabotropic glutamate 7 (mGlu 7 ) receptor belongs to the group III of mGlu receptors. Since the mGlu 7 receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may have therapeutic benefit in several CNS diseases. However, mGlu 7 remains relatively unexplored among the eight known mGlu receptors partly because of the limited availability of tool compounds to interrogate its potential therapeutic utility. Here we report the discovery of a new class of mGlu 7 allosteric agonists. Hits originating from virtual screening were followed up with further analogue searching and screening, leading to a novel series of mGlu 7 allosteric agonists. Guided by docking into a structural model of the mGlu 7 receptor the initial hit 5 was successfully optimized to analogues with comparable potencies and more attractive drug-like attributes than AMN082.
    Original languageEnglish
    Pages (from-to)1043-1054
    JournalACS Chemical Neuroscience
    Volume10
    DOIs
    Publication statusPublished - 20 Mar 2019

    Keywords

    • allosteric
    • glutamate
    • homology model
    • metabotropic
    • mGlu 7
    • PAM
    • virtual screening

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    Cid, J. M., Lavreysen, H., Tresadern, G., Pérez-Benito, L., Tovar, F., Fontana, A., & Trabanco, A. A. (2019). Computationally Guided Identification of Allosteric Agonists of the Metabotropic Glutamate 7 Receptor. ACS Chemical Neuroscience, 10, 1043-1054. https://doi.org/10.1021/acschemneuro.8b00331