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

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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 analogs of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explore 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 analogs 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, a GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4- to 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
JournalA C S Chemical Neuroscience
Issue number6
Pages (from-to)2989-3007
Number of pages19
Publication statusPublished - 19 Jun 2019

ID: 218311189