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

ACS Chem Neurosci. 2019 Jun 19;10(6):2989-3007. doi: 10.1021/acschemneuro.9b00205. Epub 2019 May 24.


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 (2 S,3 R)-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).

Keywords: CNS; Glutamate receptors; NMDA receptors; kainate; proline analogues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Design
  • Glutamate Plasma Membrane Transport Proteins / metabolism*
  • Humans
  • Ligands
  • Models, Molecular
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / pharmacology*
  • Rats
  • Receptors, Ionotropic Glutamate / metabolism*
  • Structure-Activity Relationship


  • Glutamate Plasma Membrane Transport Proteins
  • Ligands
  • Receptors, Ionotropic Glutamate
  • Proline