Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid.
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.
Hansen
J J
JJ
Department of Chemistry BC, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Nielsen
B
B
Krogsgaard-Larsen
P
P
Brehm
L
L
Nielsen
E O
EO
Curtis
D R
DR
D000818:Animals; D002415:Cats; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis*; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D014961:X-Ray Diffraction
D007202:Indicators and Reagents; D010080:Oxazoles; D011955:Receptors, Drug; D017981:Receptors, Neurotransmitter; C023366:4-bromohomoibotenic acid; D007051:Ibotenic Acid