Excitatory amino acid receptor ligands: Asymmetric synthesis, absolute stereochemistry and pharmacology of ( R)- and ( S)-homoibotenic acid

• Published in: Bioorganic & medicinal chemistry Vol. 3; no. 5; pp. 553 - 558
• Main Authors: Bischoff, F., Johansen, T.N., Ebert, B., Krogsgaard-Larsen, P., Madsen, U.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.1995
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - agonists; Animals; Cerebral Cortex - metabolism; Glutamic Acid - metabolism; Ibotenic Acid - analogs & derivatives; Ibotenic Acid - chemistry; Ibotenic Acid - metabolism; In Vitro Techniques; Kainic Acid - metabolism; Ligands; N-Methylaspartate - agonists; Radioligand Assay; Rats; Receptors, Glutamate - chemistry; Receptors, Glutamate - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(95)00044-H

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)-BrHIBO. 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. The enantiomers of homoibotenic acid (HIBO) were synthesized through diastereomeric intermediates. The absolute stereochemistry was determined chemically, the enantiomeric excess by chiral HPLC and pharmacology studied by receptor binding and electrophysiological experiments.