Excitatory amino acid agonists. Enzymic resolution, X-ray structure, and enantioselective activities of (R)- and (S)-bromohomoibotenic acid

Article abstract of DOI:10.1021/jm00130a005

The enantiomers of α-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)-α-(acetylamino)-4-bromo-3-methoxy-5-isoxazolepropionic acid 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. (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 μM) was considerably more potent than the R form (IC₅₀ = 32 μM) as an inhibitor of [³H]-(RS)-α-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 μM, 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.