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

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, GluK3preferring (GluK1/GluK3 K i 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 (K i = 0.61 μM) over GluN1/GluN2B-D (K i = 2.7−62 μM).

Kainic Acid-Based Agonists of Glutamate Receptors: SAR Analysis and Guidelines for Analog Design

“…Most recently, Bunch and Pickering reported new CPAA ( 11 ) derivatives that exhibit selectivity for GluK3 over GluK1 . Compounds 46 – 48 show low micromolar activity and deviate from the trends outlined in this review as they all lack a C4 side chain (Figure ).…”

“…69−71 Most recently, Bunch and Pickering reported new CPAA (11) derivatives that exhibit selectivity for GluK3 over GluK1. 72 Compounds 46−48 show low micromolar activity and deviate from the trends outlined in this review as they all lack a C4 side chain (Figure 11). The source of this GluK3 selectivity is still unclear; however they may indicate a different binding modality that can exploited.…”

“…Triazole 47 ’s K i is 15-fold more active for GluK3 than for GluK1. Intriguingly, tetrazole 48 binds equally well to GluK1, 2, and 3, but displays a selective antagonistic activity for GluN1 over GluN2B–D …”

A Diversity Oriented Synthesis Approach to New 2,3-trans-Substituted l-Proline Analogs as Potential Ligands for the Ionotropic Glutamate Receptors

“…C7 being sp 3 -hybridized (3f−g) most positively affected the binding affinity at the native KA receptor, with concurrent reduced affinity for native NMDA receptors. Of the 2-carboxy-3-pyrrolidine-acetic acid (CPAA) 7 analogs 3i-A/B and 3j, the 7-oxo analog 3j displayed high nanomolar affinity for native NMDA receptors, and 10− 12-fold preference in binding at GluK3, over GluK1,2.…”

“…In recent years, we have studied the 2,3- trans - l -proline core intensively as a key structural motif for the development of new ligands for the iGluRs, which display an unprecedented pharmacological profile across the multitude of iGluR subunits and their tetrameric combinations into functional iGluR subtypes. − Of the approaches taken, one central strategy was the rational design of 1a (Figure ), as a broad-acting iGlu receptor antagonist in the micromolar range . Extensive structure–activity relationship (SAR) studies of 1a eventually brought forward NMDA receptor selective antagonist 1b – d of which 1b was shown to augment the cytotoxic effect of the chemotherapeutic agent sorafenib .…”