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><sub>i</sub> = 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
