3-Substituted phenylalanines as selective AMPA- and kainate receptor ligands.
On the basis of X-ray structures of ionotropic glutamate receptor constructs in complex with amino acid-based AMPA and kainate receptor antagonists, a series of rigid as well as flexible biaromatic alanine derivatives carrying selected hydrogen bond acceptors and donors have been synthesized in order to investigate the structural determinants for receptor selectivity between AMPA and the GluR5 subtype of kainate receptors. Compounds selective for either GluR5 or AMPA receptors were identified. One particular substituent position appeared to be of special importance for control of ligand selectivity. Using molecular modeling the observed structure-activity relationships at AMPA and GluR5 receptors were deduced.
Szymańska
Ewa
E
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
Pickering
Darryl S
DS
Nielsen
Birgitte
B
Johansen
Tommy N
TN
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D008024:Ligands; D018377:Neurotransmitter Agents; D010649:Phenylalanine; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins