Role of enzymatically catalyzed 5-iodo-5,6-dihydrouracil ring hydrolysis on the dehalogenation of 5-iodouracil

Incubation of 5-iodo-5,6-dihydrouracil (IH2Ura) with soluble rat liver enzymes at 37 degrees, pH 8.2, results in the rapid release of iodide ion. The second product resulting from the carbon skeleton of the dihydropyrimidine ring system is 2-amino-2-oxazoline-5-carboxylic acid (I). Ultraviolet absorbance measurements at 225 nm, where both IH2Ura and iodide ion absorb, indicate that IH2Ura dehalogenation is a two-step process. The first step, which is enzyme-dependent, involves dihydropyrimidine amidohydrolase (EC 3.5.2.2.)-catalyzed hydrolysis of the IH2Ura ring system presumably to yield 2-iodo-3-ureidopropionate. The enzyme preparations also catalyze the hydrolysis of 5-bromo-5,6-dihydrouracil, 5,6-dihydrouracil, and 5,6-dihydrothymine, the latter two of which are the natural substrates for dihydropyrimidine amidohydrolase. The second step in IH2Ura dehalogenation involves the nonenzymatically catalyzed, pH-independent intramolecular cyclization of 2-iodo-3-ureidopropionate via nucleophilic attack of the ureido oxygen atom on carbon-2 resulting in iodide ion and the oxazoline (I) as final products. The results are discussed relative to the role of pyrimidine catabolizing enzymes in 5-halopyrimidine dehalogenation.     

Inhibition of klenow fragment (exo-) catalyzed DNA polymerization by (5R)-5,6-dihydro-5-hydroxythymidine and structural analogue 5,6-dihydro-5-methylthymidine

Oligonucleotides containing 5R-5,6-dihydro-5-hydroxythymidine (5R-3) and structural analogue 5,6-dihydro-5-methylthymidine (9) at defined sites were chemically synthesized via a method that obviates the use of NH4OH. Oligonucleotides prepared by this method were used to examine the effects of 5R-3 and 9 on the fidelity of Klenow (exo-) in vitro. The presence of lesions 5R-3 and 9 in DNA templates was shown to inhibit polymerization of primers hybridized to these templates. Inhibition was observed for both translesional synthesis and extension one nucleotide past the lesion, with the latter being more pronounced. The fidelity of Klenow (exo-) was reduced only slightly when utilizing substrates containing either dihyropyrimidine nucleotide. These results provide the first experimental verification of computational studies carried out on the effects of 3 on DNA templates, and are consistent with a structural model in which the C5-methyl group of 5R-3 adopts a pseudoaxial orientation resulting in a disruption in base stacking.     

Conformational and electronic properties of the two cis (5S,6R) and (5R,6S) diastereoisomers of 5,6-dihydroxy-5,6-dihydrothymidine: X-ray and theoretical studies

For the first time, raloxifene or alendronate was administered to rats immediately after ovariectomy for 10 months and compared with estrogen to elucidate mechanisms behind the raloxifene effects observed in nonreproductive and reproductive tissues. Specifically, 75-day-old rats were randomly selected as sham controls (Sham), ovariectomized controls (Ovx) or ovariectomized rats treated with fully efficacious doses of raloxifene (RA), 17 alpha-ethynyl estradiol (EE2) or alendronate (ABP). Lumbar vertebrae and proximal tibiae were examined by computed tomography (QCT) and by histomorphometry. Histomorphometry showed differences in bone architecture between groups when QCT densities were similar, but tibial trabecular bone analysis by QCT correlated with histomorphometry with r = .86 to .93, depending on the parameter. Both techniques confirmed that Ovx had substantially less bone than Sham, with greater loss of trabecular bone in the proximal tibia than vertebrae. Both techniques showed that RA had effects similar to but not identical with EE2 in preventing bone loss in vertebrae and tibiae. ABP partially prevented loss of bone in L-5, but was not significantly different from Ovx in the proximal tibia. This may be caused by ABP suppression of bone apposition, beyond effects observed for EE2 or RA. RA appeared to be more similar to EE2 because ABP significantly depressed bone formation (bone formation rate, mineral apposition rate) to below RA or EE2 levels, especially in L-5. Mechanical loading to failure of L-6 vertebrae showed a rank order of vertebral strength of Sham > RA > EE2 > Ovx > ABP, although significant differences were not observed between treatment groups. These data show that ABP suppression of bone formation can affect bone quality with long-term treatment. In other tissues, RA had minimal uterine effects, while significantly lowering serum cholesterol to below EE2-treated levels. Both EE2 and RA rats had significantly lower body weights than the other groups. ABP had no effect on serum lipids, uterine weight or body weight. Therefore, RA appears to have a broader range of desirable effects on bone, body weight, uteri and cholesterol than ABP or EE2 in ovariectomized rats.     

Differential behavior of (25R)-5,6-epoxyspirostan-22 alpha-O-3 beta-ol and (25R)-5,6-epoxyspirostan-22 alpha-O-3 beta, 4 beta-diol toward Dowex

The acid-catalyzed hydrolytic cleavage of the 5,6-epoxyspirostane derivatives by the cation exchange resin Dowex 50W X8 has been exploited with the goal of developing synthetic protocols toward 3,4,5,6-polyhydroxyspirostane analogs that can serve as intermediates to potential biologically active compounds. Whereas the diastereomers (25R)-5 alpha, 6 alpha-epoxyspirostan-22 alpha-O-3 beta-ol and (25R)-5 beta, 6 beta-epoxyspirostan-22 alpha-O-3 beta-ol yield two products, (25R)-6 beta-methoxyspirostan-22 alpha-O-3 beta, 5 alpha-diol and (25R)-spirostan-22 alpha-O-3 beta, 5 alpha, 6 beta-triol on Dowex treatment in water-methanol, the alpha- and beta-diastereomers of the 5,6-epoxy derivative of 3 beta, 4 beta-diol provide a single product, (25R)-3 beta, 6 beta-dihydroxy-5 alpha-spirostan-4-one, in good yields. The structures of these products have been confirmed using 1H NMR, 13C NMR, and 1H-1H J-correlated spectroscopies. Multifunctional product formation suggests tremendous utility of Dowex in steroid synthesis. The product formation has been rationalized on the basis of differential conformational constraints of the A/B rings of the different epoxides in directing the reaction course. The reaction shows an interesting example of stereoelectronic effect of a single hydroxy group in discriminating solvent participation.     

Pharmacokinetics of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1- piperazinyl)-1,4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride (DW-116), a new quinolone antibiotic in rats

The objectives of this study were to characterize the pharmacokinetics of 1-5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1- piperazinyl)-1,4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride (DW-116), a newly developed quinolone antibiotic, and to compare these kinetics with those of ciprofloxacin and rufloxacin, representative quinolone antibiotics, in rats. Rats were subjected to surgery involving catheterization of the femoral vein and artery. DW-116 (4, 20, or 200 mg/kg), ciprofloxacin (20 mg/kg), or rufloxacin (20 mg/kg) was administered either intravenously (iv) or orally. Blood samples were collected at various times and subjected to an HPLC assay for the quinolones. Temporal profiles of plasma concentration after iv administrations of DW-116 at doses of 4, 20, and 200 mg/kg exhibited an apparent multiexponential decline. In the three doses examined, systemic clearance and steady-state volume of distribution of DW-116, calculated by model-independent methods, were in the range 0.17 approximately 0.23 L/h/kg and 2.90 approximately 4.44 L/kg, respectively. When DW-116 was given orally at doses of 4, 20, or 200 mg/kg, the AUC values were nearly identical to those following iv administration, indicating an almost complete absorption (i.e., the percent bioavailability was 90.0 for 4 mg/kg, 99.0 for 20 mg/kg, and 98.3 for 200 mg/kg) in the dose range examined. The absorption of DW-116 appears to be extremely rapid because the mean residence time calculated from the oral administration data was not significantly different from that for the iv administration. At a dose of 20 mg/kg, the mean residence time for iv administered ciprofloxacin and rufloxacin was smaller than that of DW-116, indicating that DW-116 remains in the body longer than the other quinolones. Absolute percent bioavailabilities of ciprofloxacin (69.9%) and rufloxacin (84.9%) were smaller than that obtained for DW-116 (99.0%). Because it has been reported that the in vivo antibacterial activity of DW-116 is comparable or superior to that of rufloxacin and ciprofloxacin, despite the fact that the in vitro activity is significantly lower, the pharmacokinetics of this antibiotic may be responsible, at least in part, for the enhanced in vivo antibacterial activity of DW-116.     

Mechanism of inhibition of DNA (cytosine C5)-methyltransferases by oligodeoxyribonucleotides containing 5,6-dihydro-5-azacytosine

A key step in the predicted mechanism of enzymatic transfer of methyl groups from S-adenosyl-l-methionine (AdoMet) to cytosine residues in DNA is the transient formation of a dihydrocytosine intermediate covalently linked to cysteine in the active site of a DNA (cytosine C5)-methyltransferase (DNA C5-MTase). Crystallographic analysis of complexes formed by HhaI methyltransferase (M.HhaI), AdoMet and a target oligodeoxyribonucleotide containing 5-fluorocytosine confirmed the existence of this dihydrocytosine intermediate. Based on the premise that 5,6-dihydro-5-azacytosine (DZCyt), a cytosine analog with an sp3-hybridized carbon (CH2) at position 6 and an NH group at position 5, could mimic the non-aromatic character of the cytosine ring in this transition state, we synthesized a series of synthetic substrates for DNA C5-MTase containing DZCyt. Substitution of DZCyt for target cytosines in C-G dinucleotides of single-stranded or double-stranded oligodeoxyribonucleotide substrates led to complete inhibition of methylation by murine DNA C5-MTase. Substitution of DZCyt for the target cytosine in G-C-G-C sites in double-stranded oligodeoxyribonucleotides had a similar effect on methylation by M. HhaI. Oligodeoxyribonucleotides containing DZCyt formed a tight but reversible complex with M.HhaI, and were consistently more potent as inhibitors of DNA methylation than oligodeoxyribonucleotides identical in sequence containing 5-fluorocytosine. Crystallographic analysis of a ternary complex involving M.HhaI, S-adenosyl-l-homocysteine and a double-stranded 13-mer oligodeoxyribonucleotide containing DZCyt at the target position showed that the analog is flipped out of the DNA helix in the same manner as cytosine, 5-methylcytosine, and 5-fluorocytosine. However, no formation of a covalent bond was detected between the sulfur atom of the catalytic site nucleophile, cysteine 81, and the pyrimidine C6 carbon. These results indicate that DZCyt can occupy the active site of M.HhaI as a transition state mimic and, because of the high degree of affinity of its interaction with the enzyme, it can act as a potent inhibitor of methylation.     

Fluoroprostaglandins: synthesis and biological evaluation of the methyl esters of (+)-12-fluoro-, (-)-ent-12-fluoro-, (+)-15-epi-fluoro-, and (-)-ent-15 epi-12-fluoroprostaglandin F2 alpha

The synthesis and biological activity of the methyl esters of (+)-12-fluoroPGF2 alpha, (+)-15-epi-12-fluoroPGF2 alpha, (-)-ent-12-flurorPGF2 alpha, and (-)-ent-15-epi-12-fluoroPGF2 alpha are described. Each fluoroprostaglandin has been evaluated from pregnancy interruption in the hamster and smooth-muscle stimulating effects on gerbil colon and hamster uterine strips. All fluoroprostaglandins synthesized were shown to be neither substrates for the 15-hydroxyprostaglandin dehydrogenase nor inhibitors of the enzyme.     

Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.     

(R)-(-)- and (S)-(+)-Synadenol: synthesis, absolute configuration, and enantioselectivity of antiviral effect

Synthesis of (R)-(-)- and (S)-(+)-synadenol (1a and 2a, 95-96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(-)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N, N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods: (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation-elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (-)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine-adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).     

Re-face stereospecificity at C4 of NAD(P) for alcohol dehydrogenase from Methanogenium organophilum and for (R)-2-hydroxyglutarate dehydrogenase from Acidaminococcus fermentans as determined by 1H-NMR spectroscopy

The two diastereotopic protons at C4 of NAD(P)H are seen separately in 1H-NMR spectra. This fact was used to determine the stereospecificity at C4 of NAD(P) for the NADP-dependent alcohol dehydrogenase from Methanogenium organophilum and for the NAD-dependent (R)-2-hydroxyglutarate dehydrogenase from Acidaminococcus fermentans. The reduction of NADP+ with [2H6]ethanol was found to yield (4R)-[4-2H1]NADPH and the oxidation of (4R)-[4-2H1]NADH with 2-oxoglutarate to yield unlabelled [4-1H]NAD+. These results indicate that both enzymes are Re-face stereospecific at C4 of the pyridine nucleotides.     

(2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6- pentamethylpiperidin-4-yl)-2,4-pentadienamide, a novel, potent and selective inhibitor of the osteoclast V-ATPase

Optimisation of a novel series of osteoclast ATPase inhibitors led to (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6- pentamethylpiperidin-4-yl)-2,4-pentadienamide (1) that was the most potent compound in an in vitro osteoclast ATPase assay and in human bone resorption assays. Two of the possible geometric isomers have also been prepared and shown to be significantly less potent than 1.     

1-(4-硝基苯基)-3-(5,6-二甲基-1,2,4三氮唑)-三氮烯的合成及与汞的显色反应

报道了1-(4-硝基苯基)-3-(5,6-二甲基-1,2,4三氮唑)-三氮烯(NPDMTT)的合成、结构表征及其与汞的显色反应.在Trition X-100表面活性剂和pH 11.0的Na2B4O7-NaOH缓冲溶液中,该试剂与汞形成3:1的浅黄色络合物,络合物的最大负吸收峰位于530nm处,表观摩尔吸光系数为1.34×105L·mol-1·cm-1.Hg2 的浓度在0～36μg/L范围内符合比尔定律,相关系数r=0.999 8.用拟定方法测定工业废水中的汞,RSD≤1.2%,加标回收率为98.8%～101.5%.     

5-Br-PADAT和3,5-Br_2-PADAT作为络合滴定指示剂的应用

研究了 5 [(5 溴 2 吡啶 )偶氮 ] 2 ,4 二氨基甲苯和 5 [(3,5 二溴 2 吡啶 )偶氮 ] 2 ,4 二氨基甲苯作为直接滴定铜和以铜为回滴剂的指示剂的应用 ,以及以前者为指示剂滴定铜与锌等离子总量 ,并借助掩蔽剂以提高选择性 ,成功应用于铜合金等样品的分析。     

Microstructure and growth kinetics of the fibrous composite subscale formed by internal oxidation of SmCo5

The oxidation of SmCo₅ is an unusual example of selective internal oxidation in which the subscale formed consists of a composite microstructure containing samarium oxide fibers and β-cobalt. The oxide fiber size increases with oxidation temperature, and the orientation of the fibers is generally perpendicular to the subscale-alloy interface. The unusual structure results because of the high concentration of samarium in the intermetallic compound, coupled with a low solubility of samarium in metallic cobalt resulting in a subscale consisting of 39 vol pct oxide. Growth of the subscale follows the parabolic oxidation law, and the kinetics have been determined between 100 and 1125°C. The kinetics are too fast to be explained by lattice diffusion in either the oxide or the cobalt phases. Oxygen diffusion down the cobalt-oxide fiber interface appears to be the transport mechanism for this diffusion controlled process. The oxidation behavior of PrCo₅ is identical with that of SmCo₅.     

5—Br—PADAT和3,5—Br2—PTDAT作为络合滴定指示剂的应用

研究了５－「（５－溴－２－吡啶）偶氮」－２,４－二氨基甲苯和５－「（３,５－二溴－２－吡啶）偶氮」－２,４－二氨基甲苯作为直接滴定铜和以铜为回滴剂的批示剂的应用,以及以前者为指示剂滴定铜与锌等离子总量,并借助掩蔽剂以提高选择性,成功应用于铜合金等样品的分析。     

Metabolism of 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human neutrophils

We have previously shown that human polymorphonuclear leukocytes (PMNL) convert 6-trans isomers of leukotriene B4 (LTB4) to 6,11-dihydro metabolites (Powell and Gravelle (1988) J. Biol. Chem. 263, 2170-2177). In the present study, we have shown that the first step in the formation of these dihydro metabolites is oxidation of the 5-hydroxyl group to a 5-oxo group, which is catalyzed by an NADP(+)-dependent microsomal dehydrogenase enzyme. All the dihydroxyeicosanoids we investigated which contained a 5(S)-hydroxyl group followed by a 6-trans double bond were good substrates for this reaction. However, LTB4, which contains a 6-cis double bond, was not metabolized to any detectable 5-oxo products. The preferred substrate for the dehydrogenase reaction is 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5(S)-HETE), which has a Km of about 0.2 microM, compared to approx. 0.9 microM for 12-epi-6-trans-LTB4. In contrast to 5(S)-HETE, 5(R)-HETE as well as a variety of positional isomers of 5(S)-HETE are not metabolized to significant extents by the PMNL dehydrogenase. 5-Oxo-ETE and 5-oxo-15-hydroxy-ETE, which are formed from 5(S)-HETE and 5,15-diHETE, respectively, by this pathway, are potent chemotactic agents for human neutrophils, and raise intracellular calcium levels in these cells.     

Mechanism of the oxidation of 3,5,3',5'-tetramethylbenzidine by myeloperoxidase determined by transient- and steady-state kinetics

Earlier investigations of the oxidation of 3,5,3',5'-tetramethylbenzidine (TMB) using horseradish peroxidase and prostaglandin H-synthase have shown the formation of a cation free radical of TMB in equilibrium with a charge-transfer complex, consistent with either a two- or a one-electron initial oxidation. In this work, we exploited the distinct spectroscopic properties of myeloperoxidase and its oxidized intermediates, compounds I and II, to establish two successive one-electron oxidations of TMB. By employing stopped-flow techniques under transient-state and steady-state conditions, we also determined the rate constants for the elementary steps of the myeloperoxidase-catalyzed oxidation of TMB at pH 5.4 and 20 degrees C. The second-order rate constant for compound I formation from the reaction of native enzyme with H2O2 is 2.6 x 10(7) M-1 s-1. Compound I undergoes a one-electron reduction to compound II in the presence of TMB, and the rate constant for this reaction was determined to be (3.6 +/- 0.1) x 10(6) M-1 s-1. The spectral scans show that compound II accumulates in the steady state. The rate constant for compound II reduction to native enzyme by TMB obtained under steady-state conditions is (9.4 +/- 0.6) x 10(5) M-1 s-1. The results are applied to a new, more accurate assay for myeloperoxidase based upon the formation of the charge-transfer complex between TMB and its diimine final product.     

Excitatory amino acid receptor antagonists: resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA)

We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee > 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki > 1,000 microM).