Rational design, synthesis and pharmacological evaluation of the (2R)- and (2S)-stereoisomers of 3-(2-carboxypyrrolidinyl)-2-methyl acetic acid as ligands for the ionotropic glutamate receptors.
In this paper we describe the rational design, synthesis and pharmacological evaluation of two new stereoisomeric (S)-glutamate (Glu) analogues. The rational design was based on hybrid structures of the natural product kainic acid, a synthetic analogue CPAA and the high-affinity Glu analogue SYM2081. Pharmacological evaluation of the two stereoisomers revealed that one stereoisomer showed a subtype selectivity profile with low micromolar affinity for GluK1 and GluK3 and a 10- to 15-fold lower affinity for GluK2. The other stereoisomer displayed full selectivity for the KA over AMPA and NMDA receptors (GluK1-3: 0.39, 0.51 and 0.099 µM, respectively).
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Julie L
JL
Rasmussen
Morten
M
Storgaard
Darryl S
DS
Pickering
Lennart
L
Bunch
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D018698:Glutamic Acid / Q000031:analogs & derivatives; D007608:Kainic Acid / Q000737:chemistry; D008024:Ligands; D011485:Protein Binding; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013816:Thermodynamics; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor
D000085:Acetates; D018698:Glutamic Acid; D007608:Kainic Acid; D008024:Ligands; D058468:Receptors, Ionotropic Glutamate; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor