Excitatory amino acid receptor ligands: asymmetric synthesis, absolute stereochemistry and pharmacology of (R)- and (S)-homoibotenic acid.
The (R)- and (S)-forms of 2-amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) were synthesized, using (S)-BOC-phenylalanine as a chiral auxiliary and their absolute stereochemistry correlated with that of (R)-Br-HIBO. The enantiomeric excesses for (R)-HIBO (1) (> 99.5%) and (S)-HIBO (2) (99.5%) were determined using chiral HPLC. Whereas compounds 1 and 2 were equipotent inhibitors of the binding of [3H]glutamic acid in the presence of calcium chloride, 2 showed AMPA agonist activity and 1 very weak NMDA agonist activity.
Bischoff
F
F
PharmaBiotec Research Center, Royal Danish School of Pharmacy, Copenhagen.
Johansen
T N
TN
Ebert
B
B
Krogsgaard-Larsen
P
P
Madsen
U
U
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000378:metabolism; D008024:Ligands; D016202:N-Methylaspartate / Q000819:agonists; D011869:Radioligand Assay; D051381:Rats; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000819:agonists
D008024:Ligands; D017470:Receptors, Glutamate; D007051:Ibotenic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; C023364:homoibotenic acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid