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

Abstract

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.

O-Methyl-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol Hydrochloride, O-Me-THPO.HCl

“…Crystal data (3) 112.8(2) 1.425 (3) 112.6(2) 1.420 (3) 112.9(2) References: AMIOXO, Brehm (1977); HAPIOX, Brehm & KrogsgaardLarsen (1974); HMUSCM, ISAZOL, Brehm & Larsen (1976); DECJAW/DECJAW01, Krogsgaard-Larsen et al (1985); DEVFEP, Brehm et al (1985); GASKUG, Madsen et al (1988); RSAMPA, Honor6 & Lauridsen (1980); SEBFUA, Hansen et al (1989); OPOXAZ/OPOXAZ01, Biagini et al (1969a,b); (R)-APPA, Ebert et al (1994).…”

Stereostructure–activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

“…34 These structures strongly suggest that the hydrogen bond architecture through water molecules and involving the isoxazole hydroxy group of (S)-Br-HIBO and Tyr702 of the GluR2 ligand binding domain is crucial for the observed subtypeselectivity of (S)-Br-HIBO, 34 as previously suggested by Banke et al 70 The very low AMPA receptor affinities observed for (R)-HIBO and (R)-Br-HIBO (Table 3) most likely reflect the enantiomeric purity obtained, rendering the HIBO analogs highly stereoselective at AMPA receptors. However, both the S-and R-enantiomers of the HIBO analogs generally show affinity in CaCl 2 -dependent [ 3 H]Glu binding and potent activity after quisqualic acid priming in electrophysiological experiments, 67,68,71 suggesting interaction with transport mechanisms different from the synaptic reuptake systems. Even though (R)-Bu-HIBO was shown to be inactive per se at AMPA receptors, coadministration of (S)-Bu-HIBO with a fixed concentration of (R)-Bu-HIBO markedly potentiated the concentration-response curve obtained in the cortical wedge preparation (Fig.…”

Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans‐Tris(homoglutamic) acids

“…10,11 The synthesis of cyclic amino acids became a key issue within rational drug design and structure -activity relationship (SAR) studies (Fig. 1).…”