Premium
Rational Design, Synthesis and Pharmacological Evaluation of the (2 R )‐ and (2 S )‐Stereoisomers of 3‐(2‐Carboxypyrrolidinyl)‐2‐methyl Acetic Acid as Ligands for the Ionotropic Glutamate Receptors
Author(s) -
Rasmussen Julie L.,
Storgaard Morten,
Pickering Darryl S.,
Bunch Lennart
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000543
Subject(s) - ionotropic effect , acetic acid , chemistry , glutamate receptor , stereochemistry , rational design , biochemistry , biology , receptor , genetics
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 µ M , respectively).