TY - JOUR
T1 - Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors
AU - Szymańska, Ewa
AU - Nielsen, Birgitte
AU - Johansen, Tommy Nørskov
AU - Cuñado Moral, Anna Maria
AU - Pickering, Darryl S
AU - Szczepańska, Katarzyna
AU - Mickowska, Anna
AU - Kieć-Kononowicz, Katarzyna
PY - 2017
Y1 - 2017
N2 - In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (–)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R-isomer showing Ki of 1.71 µM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)i receptors in TEVC electrophysiological experiments (Kb = 2.13 µM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications.
AB - In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (–)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1'-biphenyl]-3-yl)propanoic acid, the expected R-isomer showing Ki of 1.71 µM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)i receptors in TEVC electrophysiological experiments (Kb = 2.13 µM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications.
U2 - 10.1016/j.ejmech.2017.07.007
DO - 10.1016/j.ejmech.2017.07.007
M3 - Journal article
C2 - 28738307
SN - 0223-5234
VL - 138
SP - 874
EP - 883
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -