Discovery of a new class of ionotropic glutamate receptor antagonists by the rational design of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid.
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.
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Ann M
AM
Larsen
Raminta
R
Venskutonytė
Elena Antón
EA
Valadés
Birgitte
B
Nielsen
Darryl S
DS
Pickering
Lennart
L
Bunch
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery / Q000639:trends*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D007313:Insecta; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014982:Xenopus laevis
D018691:Excitatory Amino Acid Antagonists; D011759:Pyrrolidines; D058468:Receptors, Ionotropic Glutamate