Synthesis and receptor binding affinity of new selective GluR5 ligands

Two hybrid analogues of the kainic acid receptor agonists. 2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA) and (2S,4R)-4-methylglutamic acid ((2S,4R)-4-Me-Glu), were designed, synthesized, and characterized in radioligand binding assays using cloned ionotropic and metabotropic glutamic acid receptors. The (S)-enantiomers of E-4-(2,2-dimethylpropylidene)glutamic acid ((S)-1) and E-4-(3,3-dimethylbutylidene)glutamic acid ((S)-2) were shown to be selective and high affinity Glu R5 ligands, with K, values of 0.024 and 0.39 muM. respectively, compared to K-i values at GluR2 of 3.0 and 2.0 muM, respectively. Their affinities in the [H-3]AMPA binding assay on native cortical receptors were shown to correlate with their GluR2 affinity rather than their GluR5 affinity. No affinity for GluR6 was detected (IC50 > 100 muM). (C) 2001 Elsevier Science Ltd. All rights reserved.