Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

• Published in: ACS chemical neuroscience 2011-02, Vol.2 (2), p.107-114
• Main Authors: Larsen, Ann M, Venskutonytė, Raminta, Valadés, Elena Antón, Nielsen, Birgitte, Pickering, Darryl S, Bunch, Lennart
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Crystallography, X-Ray; Drug Design; Drug Discovery - trends; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - metabolism; Excitatory Amino Acid Antagonists - pharmacology; Female; Insecta; Protein Binding - physiology; Protein Structure, Secondary; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Rats; Receptors, Ionotropic Glutamate - antagonists & inhibitors; Receptors, Ionotropic Glutamate - metabolism; Xenopus laevis
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/cn100093f

The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1−5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.