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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 (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).

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Poulie CBM,Alcaide A,Krell-Jørgensen M,Larsen Y,Astier E,Bjørn-Yoshimoto WE,Yi F,Syrenne JT,Storgaard M,Nielsen B,Frydenvang KA,Jensen AA,Hansen KB,Pickering DS,Bunch L

doi

10.1021/acschemneuro.9b00205

subject

Has Abstract

pub_date

2019-06-19 00:00:00

pages

2989-3007

issue

6

issn

1948-7193

journal_volume

10

pub_type

杂志文章

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