Structure–Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2<i>S</i>,3<i>R</i>)‑3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

Herein we describe the first structure–activity relationship study of the broad-range iGluR antagonist (2<i>S</i>,3<i>R</i>)-3-(3-carboxyphenyl)­pyrrolidine-2-carboxylic acid (<b>1</b>) by exploring the pharmacological effect of substituents in the 4, 4′, or 5′ positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4′ position <b>2a</b> which induced a preference in binding affinity for homomeric GluK3 over GluK1 (<i>K</i>_i = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: <b>2e</b> in GluA2-LBD and <b>2f</b> in GluK1-LBD, both at 1.9 Å resolution. Compound <b>2e</b> induces a D1–D2 domain opening in GluA2-LBD of 17.3–18.8° and <b>2f</b> a domain opening in GluK1-LBD of 17.0–17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of <b>2e</b> and <b>2f</b> shows a similar binding mode as kainate. The 3-carboxyphenyl ring of <b>2e</b> and <b>2f</b> forms contacts comparable to those of the distal carboxylate in kainate