Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Ann Møller Larsen, Raminta Venskutonyte, Elena Antón Valadés, Birgitte Nielsen, Darryl S Pickering, Lennart Bunch

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    Abstract

    The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/
    or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we
    present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 µM; KA, 22 µM; NMDA 6 µM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 µM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a Kb of 11.4 µM.
    Original languageEnglish
    JournalACS Chemical Neuroscience
    Volume2
    Issue number2
    Pages (from-to)107-114
    Number of pages8
    ISSN1948-7193
    DOIs
    Publication statusPublished - 4 Nov 2011

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