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

作者：Larsen Ann M; Venskutonyte Raminta; Valades Elena Anton; Nielsen Birgitte; Pickering Darryl S; Bunch Lennart^*

来源：ACS Chemical Neuroscience, 2011, 2(2): 107-114.

DOI：10.1021/cn100093f

• Glutamate receptors
• kainic acid receptors
• antagonist
• rational design

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,mu M; KA, 22 mu M; NMDA 6 mu M), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 mu M, 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 mu M.

• 出版日期2011-2