title: Synthesis and receptor binding affinity of new selective GluR5 ligands.
abstract: 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 GluR5 ligands, with Ki values of 0.024 and 0.39 microM, respectively, compared to Ki values at GluR2 of 3.0 and 2.0 microM. respectively. Their affinities in the [3H]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 microM).
authors.affiliation: Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, Copenhagen.
authors.forename: L
authors.initials: L
authors.lastname: Bunch
authors.forename: T H
authors.initials: TH
authors.lastname: Johansen
authors.forename: H
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: T B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: T N
authors.initials: TN
authors.lastname: Johansen
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: U
authors.initials: U
authors.lastname: Madsen
mesh_terms: D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D018091:Receptors, AMPA / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D005971:Glutamates; D007202:Indicators and Reagents; D008024:Ligands; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C436506:4-(2,2-dimethylpropylidene)glutamic acid; C436507:4-(3,3-dimethylbutylidene)glutamic acid; C046105:4-methylglutamic acid