Synthesis and receptor binding affinity of new selective GluR5 ligands

TY - JOUR

T1 - Synthesis and receptor binding affinity of new selective GluR5 ligands

AU - Bunch, L

AU - Johansen, T H

AU - Bräuner-Osborne, Hans

AU - Stensbøl, T B

AU - Johansen, T N

AU - Krogsgaard-Larsen, P

AU - Madsen, U

PY - 2001/4

Y1 - 2001/4

N2 - 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).

AB - 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).

KW - Cell Line

KW - Chromatography, High Pressure Liquid

KW - Glutamates

KW - Humans

KW - Indicators and Reagents

KW - Ligands

KW - Magnetic Resonance Spectroscopy

KW - Receptors, AMPA

KW - Receptors, Kainic Acid

KW - Tumor Cells, Cultured

U2 - 10.1016/S0968-0896(00)00304-7

DO - 10.1016/S0968-0896(00)00304-7

M3 - Journal article

C2 - 11354670

SN - 0968-0896

VL - 9

SP - 875

EP - 879

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 4

ER -