Design and Synthesis of 2,3- trans-Proline Analogues as Ligands for Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters

Christian B.M. Poulie, Anna Alcaide, Mikkel Krell-Jørgensen, Younes Larsen, Eloi Astier, Walden E. Bjørn-Yoshimoto, Feng Yi, Jed T. Syrenne, Morten Storgaard, Birgitte Nielsen, Karla A. Frydenvang, Anders A. Jensen, Kasper B. Hansen, Darryl S. Pickering, Lennart Bunch

Research output: Contribution to journalArticlepeer-review

Abstract

Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ϵ-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor (Ki = 0.61 μM) over GluN1/GluN2B-D (Ki = 2.7-62 μM).

Original languageEnglish
Pages (from-to)2989-3007
Number of pages19
JournalACS Chemical Neuroscience
Volume10
Issue number6
DOIs
StatePublished - Jun 19 2019

Keywords

  • CNS
  • Glutamate receptors
  • NMDA receptors
  • kainate
  • proline analogues

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