Article date: 1989/10/1
PubMed ID: 2552114
Journal name: Journal of medicinal chemistry (ISSN: 0022-2623)
The enantiomers of alpha-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid (4-bromohomoibotenic acid, Br-HIBO, 1) a selective and potent agonist at one class of the central (S)-glutamic acid receptors, were prepared with an enantiomeric excess higher than 98.8% via stereoselective enzymic hydrolysis of (RS)-alpha-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid (4) using immobilized aminoacylase. The absolute configuration of the enantiomers of Br-HIBO was established by X-ray crystallographic analysis, which confirmed the expected preference of the enzyme for the S form of the substrate 4. (S)- and (RS)-Br-HIBO were potent neuroexcitants on cat spinal neurones in vivo, while (R)-Br-HIBO was a very weak excitant. Correspondingly, the S enantiomer of Br-HIBO (IC50 = 0.34 microM) was considerably more potent than the R form (IC50 = 32 microM) as an inhibitor of [3H]-(RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([ 3H]AMPA) binding to rat brain synaptic membranes in vitro. In contrast, (S)- and (R)-Br-HIBO were approximately equipotent (IC50 values of 0.22 and 0.15 microM, respectively) as inhibitors of [3H]-(S)-glutamic acid binding in the presence of CaCl2. The enantiomers of Br-HIBO showed no significant affinity for those binding sites on rat brain membranes which are labeled by [3H]kainic acid or [3H]-(R)-aspartic acid.
Author List: Hansen J J, Nielsen B, Krogsgaard-Larsen P, Brehm L, Nielsen E O, Curtis D R
Publication Types: Journal Article; Research Support, Non-U.S. Gov't
Substances mentioned in the article: Indicators and Reagents; Oxazoles; Receptors, Drug; Receptors, Neurotransmitter; 4-bromohomoibotenic acid; Ibotenic Acid;
Mesh terms: Animals; Cats; Cell Membrane/metabolism; Cerebral Cortex/metabolism; Ibotenic Acid/analogs & derivatives; Indicators and Reagents; Interneurons/drug effects; Models, Molecular; Molecular Conformation; Molecular Structure; Oxazoles/chemical synthesis; Rats; Receptors, Drug/drug effects; Receptors, Neurotransmitter/drug effects; Spinal Cord/drug effects; Stereoisomerism; Structure-Activity Relationship; Synaptosomes/metabolism; X-Ray Diffraction;