N. Krogsgaard-Larsen, M. Storgaard, C. Møller, C.S. Demmer, J. Hansen, L. Han, R.N. Monrad, B. Nielsen, D. Tapken, D.S. Pickering, J.S. Kastrup, K. Frydenvang, and L. Bunch (2015).
Structure–activity relationship study of ionotropic glutamate receptor antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid.
Journal of Medicinal Chemistry 58(15): 6131-6150.
doi: 10.1021/acs.jmedchem.5b00750
Herein we describe the first structure–activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) 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 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1–D2 domain opening in GluA2-LBD of 17.3–18.8° and 2f a domain opening in GluK1-LBD of 17.0–17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.