DIHYDROMUSCIMOL, THIOMUSCIMOL AND RELATED HETEROCYCLIC COMPOUNDS AS GABA ANALOGUES

A series of heterocyclic GABA analogues related to muscimol (5-aminomethyl-3-isoxazolol) were tested as depressants of the firing of GABA sensitive neurones on the cat spinal cord, and as inhibitors of the sodium-independent binding of GABA to rat brain membranes. Furthermore, the compounds were examined as inhibitors of GABA uptake into rat brain slices and as inhibitors of the activities of the GABA-metabolizing enzymes L-glutamate 1-carboxylyase and GABA:2-oxoglutarate aminotransferase. Dihydromuscimol [(RS)-4,5-dihydromuscimol] and thiomuscimol (5-aminomethyl-3-isothiazolol) were approximately equipotent to muscimol as bicuculline-sensitive depressants of neuronal firing and as inhibitors of GABA binding. The structurally related compounds isomuscimol (3-aminomethyl-5-isoxa-zolol) and azamuscimol (5-aminomethyl-3-pyrazolol) were much weaker than muscimol as GABA agonists. The affinity of the compounds for GABA receptor sites in vitro is in agreement with their relative potency as GABA receptor agonists in vivo. The rat brain synaptic membranes used for the GABA receptor binding studies were prepared by two procedures, which were shown to have a pronounced influence on the observed potency of the inhibitors of GABA binding. The compounds were weak or inactive as inhibitors of the uptake of GABA into rat brain slices and of the activity of GABA: 2-oxoglutarate aminotransferase in vitro. Azamuscimol and 2-methylaza-muscimol were moderately potent inhibitors.of the activity of L-glutamate 1-carboxylyase in vitro. This inhibition by azamuscimol was timedependent following pseudo-first-order kinetics, consistent with azamuscimol acting as a catalytic inhibitor. The structure of the heterocyclic rings of these zwitterionic compounds is a factor of critical importance for interaction with GABA receptors. The present structure-activity analysis demonstrates that heterocyclic GABA analogues having a high degree of delocalization of the negative charges have low affinity for the GABA receptors.     

动物气味的顶空取样技术及其在水貂肛腺成分分析中的应用

我们设计了一种用于动物气味的顶空 (headspace)取样装置 ,并结合溶剂解吸附和气质联用技术 ,通过对水貂 (Mustelavision)肛腺分泌物的挥发性成分的分析验证这种装置的可行性。出现 5个气谱峰 ,对应的质谱显示其分子量和分子式依次为峰 1:10 2 (C5H10 S)、峰 2 :10 4(C5H12 S)、峰 3:10 2 (C5H10 S)、峰 4:136(C5H12 S2 )和峰 5 :134 (C5H10 S2 )。峰 1、峰 3和峰 5分别为以前研究所鉴定出的 3种主要成分 :2 ,2 二甲基硫代环丁烷、2 乙基硫代环丁烷和 3,3 二甲基 1,2 二硫代环戊烷 ,2 ,2 二甲基硫代环丁烷为优势成分 ,组成无性别间差异。这些结果与以前研究一致 ,说明了这种顶空取样装置的可靠性。峰 2和峰 4两种成分以前在水貂肛腺中未曾发现 ,初步分析可能分别为 3 甲基 1 丙基硫醇和 1,5 戊二硫醇。尽管这两个成分有待进一步分析确定 ,但可以肯定分子量为 10 4和 136的成分不仅在水貂肛腺分泌物中没有发现过 ,而且在已经研究过的鼬属动物和食肉类的肛腺中都未发现过 ,能检测出更多的成分 ,说明这种方法的可靠性很高。     

SYNTHESIS AND IN VITRO CYTOTOXIC AND ANTIVIRAL ACTIVITIES OF 1-(2,5,6-TRIDEOXY-6-HALOGENOHEPT-5-ENOFURANURONONITRILE)THYMINE AND DERIVATIVES

ABSTRACT

All 1-(2,5,6-trideoxy-6-halogenohept-5-enofuranurononitrile)thymine and their 3′-O-TBDMS derivatives have been prepared and their configuration established. Some of these compounds are endowed with a cytotoxic or cytostatic activity in cell culture. The single most important factor affecting the cytotoxicity of these compounds is the presence on the molecule of a soft (electrofugal) halogen atom.     

STIMULATION OF PIRIFORM- AND NEO-CORTICAL TISSUES IN AN IN VITRO FLOW-SYSTEM: METABOLIC PROPERTIES AND RELEASE OF PUTATIVE NEUROTRANSMITTERS

Abstract— (1) Multiple samples from the piriform cortex and neocortex of the guinea pig were maintained in separate incubation vessels through which incubation solutions based on Krebs-Ringer bicarbonate glucose media were caused to flow for chosen periods at specified rates.
(2) The tissues were held in defined positions in relation to electrodes; in some experiments electrical stimuli were applied and in others incubation media were changed with respect to their oxygen, K⁺ or glutamate content.
(3) With media flowing at 3–4 ml/min, the incubated tissues were similar in contents of K salts and phosphocreatine, and in rate of glycolysis to those incubated in non-flowing media. The tissues responded to electrical stimulation by increase in glycolysis and decrease in phosphocreatine and K content.
(4) During pre-incubation periods in non-flowing media, samples of piriform cortex were exposed to solutions containing ³H-labelled glycine, noradrenaline or 5-hydroxytry-ptamine and on anlaysis were found to contain the labelled compounds at concentrations four to seven times those of the surrounding media. The labelled compounds were gradually released into the flowing incubation media, and the release of noradrenaline and 5-hydroxytryptamine was accelerated by electrical stimulation.
(5) Release of the two bases was also modified by added reagents and the course of their release is discussed in relation to other metabolic changes concomitantly observed.     

薯蓣皂甙元丁二酸单酯氨基酸盐的合成及其动物实验——薯蓣皂甙元衍生物的研究I

以薯蓣皂甙元丁二酸单酯为原料,经过与氨基酸缩合,合成了5个新化合物,4—L—(N—丁二酸—2—基)胺基—4—氧代丁酸薯蓣皂甙元酯二钠盐(1),4—(N—乙酸—2—基)胺基—4—氧代丁酸薯蓣皂甙元酯钠盐(2),4—L(N—(5—胍基)戊酸—2—基)胺基—4—氧代丁酸薯蓣皂甙元酯醋酸盐(3),4—(N—(3—咪唑-4—基)丙酸—2—基)胺基—4—氧代丁酸薯蓣皂甙元酯醋酸盐(4),4—(N—戊二酸—2—基)胺基—4—氧代丁酸薯蓣皂甙元酯二钠盐(5),并对其进行了结构鉴定,同时发现这5个化合物对大鼠都具有抗心肌梗死活性。     

FLAVONOID CHEMISTRY AND SYSTEMATICS OF TITHONIA (COMPOSITAE)

Twenty-four flavonoid compounds, including chalcones and aurones, are reported from 13 taxa of Tithonia. Pedunculin (4′, 6, 7-trimethoxy, 5, 8-dihydroxyflavone), also is characterized. The distribution of these compounds is compared to the existing classification of the genus based primarily on morphological data. By comparison with the previously proposed phylogeny of the genus, the evolution of the flavonoid system may be elucidated. It is proposed that the ancestral stock of Tithonia had flavonols, di- and tri-methoxyflavones, and 6-methoxyflavones. From this ancestral stock, a number of trends have occured in derivative taxa. These trends are: 1) a maintenance of a diversity of compounds in several evolutionary lines, 2) a reduction in the number of methoxyl substitutions, and 3) the elaboration of 5-deoxyflavones and flavonols.     

SYNTHESIS OF 1-(2-HYDROXY-3-METHOXYPROPYL)URACILS AND THEIR ACTIVITY AGAINST L1210 AND MACROPHAGE RAW 264.7 CELLS

ABSTRACT

The title compounds were obtained from appropriate 5-substituted uracil derivatives and 1,2-oxy-3-methoxypropane in the presence of sodium hydride. Under similar conditions 5-iodouracil gave 2-methoxymethyl-2,3-dihydro-oxazolo[3,2-c]pyrimidine-5,7-dione as a result of intramolecular cine type nucleophilic substitution. Cytotoxicity of 1-(2-hydroxy-3-methoxypropyl)-5-substituted uracil derivatives against L1210 and macrophage RAW 264.7 cells in vitro was examined.     

EVALUATION OF BITTERNESS AND ASTRINGENCY OF (+)-CATECHIN AND (-)-EPICATECHIN IN RED WINE AND IN MODEL SOLUTION

Two stereoisomeric phenolic compounds, (+)-catechin and (-)-epicatechin, were rated for perceived intensity of oral astringency and bitterness by trained judges using the scalar method. Mouth drying and mouth roughening were also assessed, since they are often associated with astringency. Amounts of 375, 750 and 1500 mg/L of each compound were tasted in red wine, and in a model system, similar in composition to a dry table wine. Preliminary tests showed that these concentrations were above the threshold level but within the range found in wine. A control sample (model solution or wine without the addition of the above phenolic compounds) was also evaluated. The results showed that the two compounds were both bitter and astringent. The high (-)-epicatechin concentration was significantly more bitter and astringent than the equal concentration of (+)-catechin in the model solution. Mouth drying and roughening ratings showed a similar increasing pattern with the ratings of astringency particularly at the higher concentrations. However, these attributes were rated differently from astringency suggesting that although they contribute to astringency, they are not subsumed by it.     

SYNTHESIS AND ADENOSINE RECEPTOR AFFINITY AND POTENCY OF 8-ALKYNYL DERIVATIVES OF ADENOSINE

Adenosine derivatives bearing different (ar)alkynyl chains at the 8-position were synthesized and tested at human adenosine receptors. Binding studies showed that all compounds possess affinity for the A₃ subtype in the high nM range. Moreover, guanosine 5′-O-(3-[³⁵S]thio)triphosphate binding assay indicated that the 8-alkynyl adenosines behaved as antagonists of NECA at A₃ receptors.     

薯蓣皂甙元氨基酸酯的合成及其动物实验--薯蓣皂甙元衍生物的研究Ⅱ

以薯蓣皂甙元为原料,经过与氨基酸缩合,合成了6个新化合物,甘氨酸薯蓣皂甙元酯(1),DL-组氨酸薯蓣皂甙元酯醋酸盐(2),L-赖氨酸薯蓣皂甙元酯(3),N-L-赖氨酰基甘氨酸薯蓣皂甙元酯醋酸盐(4),N-L-精氨酰基甘氨酸薯蓣皂甙元酯醋酸盐(5),N-DL-组氨酰基甘氨酸薯蓣皂甙元酯醋酸盐(6),并对结构进行了鉴定。同时发现这6个化合物具有抗大鼠实验性心肌梗死作用。     

STUDIES OF VANDADIUM-BROMOPEROXIDASE USING SURFACE AND CORTICAL PROTOPLASTS OF MACROCYSTIS PYRIEFERA (PHAEOPHYTA)1

Aqueous Tri-SO₄ buffer (pH 8.3) extracts of cortical and surface protoplasts of Macrocystis pyrifera (L.) C. Ag. Catalyzed the bromination of monochlorodimedone (2-chloro-5, 5-dimethyl-1, 3-dimedone, MCD) in the presence of hydrogen peroxide and bromide. The apparent bromo-peroxidase activity as measured by the bromination of MCD was inhibited by the presence of endogenous compounds which are probably polyphenolics compounds (i.e. polymers of phloroglucinol) or other inhibitors. The bromoperoxidase activity of the protoplast extracts increased substantially when the extracts were washed extensively with Tris-SO₄ buffer (pH 8.3) by ultrafiltration. The bromoperoxidase activity of both surface and cortical protoplast extracts was dependent on the presence of vanadium, indicating that the bromoperoxidase present in cortical and surface cells of M. pyrifera is vanadium-bromoperoxidase. Halogenated compounds constitute one of the most significant classes of marine natural products. Since bromoperoxidases are assumed to be involved in the biosynthesis of these compounds, elucidation of the location of BrPO with in the algal tissue is important.     

SYNTHESIS AND BIOLOGICAL ACTIVITY OF 2-FLUORO ADENINE AND 6-METHYL PURINE NUCLEOSIDE ANALOGS AS PRODRUGS FOR SUICIDE GENE THERAPY OF CANCER

A novel series of 6-methylpurine nucleoside derivatives with substitutions at 5′-position have been synthesised. These compounds bear a 5′-heterocycle such as triazole or a imidazole with a two carbon chain, and an ether, thio ether or amine. To extend the SAR study of 2-fluoroadenine and 6-methyl purine nucleosides, their corresponding α–linker nucleosides with l-xylose and l-lyxose were also synthesized. All of these compounds have been evaluated for their substrate activity with E. coli PNP.     

Biosynthesis and Metabolism of Indol-3yl-acetic Acid: I. THE NATIVE INDOLES OF BARLEY AND TOMATO SHOOTS

Barley and tomato shoots were examined quantitatively for naturally-occurringindole compounds. Both tissues were found to contain detectablelevels of indol-3yl-acetic acid (IAA), indol-3yl-aldehyde, tryptamine,5-hydroxytryptamine and malonyltryptophan. Tomato shoots alsocontained small amounts of indol-3yl-lactic acid and tryptophol.These two compounds were absent in barley, but this tissue containedsignificant quantities of 3 -aminomethylindole, 3-methylaminomethylindole,gramine, N-methyltryptamine and 5-hydroxy-N-methyltryptamine.The possible importance of these compounds in the biosynthesisof IAA, or in the formation of alkaloids, is discussed.     

不同浓度MNP与水稻种子萌发和幼苗生长间的相关性研究

MNP（2-methoxy-5-nitro-phenal的钠盐)是一种植物生长调节剂,它是笔者参照类似物的合成原理和方法研制而成。本文研究了MNP对水稻种子萌发和幼苗生长的作用,从而为合成物MNP在农业上的应用。提供了科学依据。     

AFFINITIES OF GIDAZEPAM AND ITS ANALOGS FOR MITOCHONDRIAL BENZODIAZEPINE RECEPTORS

ABSTRACT

Mitochondrial benzodiazepine receptors (MBRs) participate in many physiological processes, such as calcium flow regulation, proliferative and respiratory cell functions, mitochondrial steroidogenesis and adaptational reactions to stress. We have found that the selective anxiolytic gidazepam has a higher affinity for CNS MBRs as compared to central benzodiazepine receptors. The ability of gidazepam to bind to MBRs probably underlies a wide spectrum of its pharmacological effects. We have studied affinities of gidazepam analogs for CNS MBRs in search for the ligands possessing higher affinity and selectivity. The experiments were carried out with male Wistar rats weighing between 200–220?g. Affinities of the investigated compounds were assessed on their ability to displace radioligand Ro5-4864 from its specific binding sites on MBRs of rat brain. Within the series of tested compounds three substances comparable on affinity with Ro5-4864 were found. Experimental results have shown that the presence of chlorine atom in o-position of 5-phenyl substituent leads to a 10 to 15-fold increase in affinity for CNS MBRs. We have also found that the essential contribution in affinity of the investigated series is brought by lipophilicity of substituent in 1N-position. Our data may be useful in design and synthesis of novel potent selectively acting ligands of CNS MBRs.     

黑蝗对植物气味及其挥发性化合物的嗅觉反应(英文)

本文使用触角电位技术研究了黑蝗雄虫的嗅觉反应,测试的材料包括5种植物叶片、9种植物挥发性气味化合物及它们的定量混合物。在5种植物材料中,路易斯安纳蒿和紫花苜蓿能引起更大的电位反应,而3种禾本科植物的反应相对较小。在绿色气味化合物中,6-碳醇类如E-2-hexen-l-ol和E-3-hexen-l-ol导致最高的电位反应,而pentenol、3-pentanone与空白对照间并无明显差异。在3种或4种挥发性化合物的混合物中,没有含pentenol的组合总是引起较高的电位。因此,该项研究证明pentenol和3-pentanone在这种多食性黑蝗的嗅觉定位中所起的作用不明显。另外,结合触角电位的数据资料,作者讨论了寄主植物挥发性化合物在该种蝗虫定位和选择寄主植物方面的作用。     

CONCENTRATIONS OF ENERGY METABOLITES AND CYCLIC NUCLEOTIDES DURING AND AFTER BILATERAL ISCHEMIA IN THE GERBIL CEREBRAL CORTEX

Abstract— The concentrations of metabolites which reflect energy production or use ( P -creatine, ATP. ADP. 5'AMP, glucose, glycogen and lactate) and cyclic nucleotides (cyclic AMP and cyclic GMP) were measured in gerbil cortex during ischemia and recirculation. Bilateral ischemia of the gerbil brain was chosen as a model to ensure the assessment of short periods of ischemia without ambiguity. The metabolites and cyclic nucleotides were measured after, 1, 5. 20. 30 and 60 min of ischemia; and 1, 5, 30, 60 and 360 min after circulation was reestablished. The greatest changes in metabolites and cyclic nucleotides due to ischemia occurred during the 1st min; ischemia of longer duration had little further effect. However, the restoration of the metabolic profile was altered by the duration of the ischemic period. In general, the longer the period of ischemia, the slower the replenishment of high-energy phosphate compounds and energy sources. Cyclic AMP increased 5- to 13-fold during ischemia; cyclic GMP decreased to as little as one-fifth control values 60min after occlusion. During recirculation, cyclic AMP increased as much as 100-fold, while cyclic GMP increased up to 6-fold. The temporal derangements in cyclic nucleotide concentrations coincide with the loss and restoration of cortical activity; a possible mechanism has been suggested.     

1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: synthesis, analgesic-anti-inflammatory and antimicrobial activities

Acetic acid hydrazide containing 5-methyl-2-benzoxazolinone (4) was synthesized by the condensation of 2-(5-methyl-2-benzoxazolinone-3-yl)acetate with hydrazine hydrate. Thiosemicarbazide derivatives (5a-5d) were afforded by the reaction of corresponding compound 4 with substituted isothiocyanates. The cyclization of compounds 5a-5d in the presence of triethylamine resulted in the formation of compounds 6a-6d containing 1,2,4-triazole ring. On the other hand, the treatment of compounds 5a-5d with orthophosphoric acid caused the conversion of side chain of compounds 5a-5d into 1,3,4-thiadiazole ring: thus, compounds 7a-7c were obtained. The treatment of compound 4 with aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (8a-8e). The structures of the compounds were elucidated by spectral and elemental analysis. While most compounds were exhibiting high activity in the analgesic-anti-inflammatory field, most of them were found to be inactive against bacteria and fungi.     

PHYTOTOXICITY OF FUNGICIDES AND BACTERICIDES IN ORCHID CULTURE MEDIA

A number of fungicides, bactericides and dual-action substances were screened for phytotoxicity in vitro using Cattleya aurantiaca and Stanhopea occulata (Orchidaceae) seedlings. Of the 25 compounds screened, ten (each at only one concentration) were employed in nine different combinations for nonsterile in vitro cultures of Cattleya aurantiaca seedlings: Amphotericin B, 10 ppm; Benlate, 50 ppm; Dowicide, 5 ppm; Ethirimol, 50 ppm; Gentamicin, 50 ppm; Nystatin, 25 ppm; PCNB, 100 ppm; Penicillin G, 100 ppm; Sodium omadine, 5 ppm; and Vancomycin, 50 ppm. All nine combinations prevented contamination, but had different effects on seedling development.     

EVALUATION AND APPLICATIONS OF ODOR PROFILING

An odor profiling procedure was developed based on the ASTM odor profiling method. This modified procedure involved using approximately twenty panelists. Panel sessions and data collection were controlled by computer. The results obtained by this panel compared favorably to results obtained by the ASTM panel for which 150 panelists evaluated each compound, indicating that a small panel can be used to produce replicable results. Statistical methods of finding similarities and dissimilarities among compounds using profile data are discussed and compared to results from a multidimensional scaling (MDS) study in which degrees of differences among compounds were judged directly. These results indicate that profile data can be used to define and map the degree of similarity/dissimilarity among compounds, as well as to define the sensory dimensions on which these compounds differ. The use of factor analysis to study the underlying sensory dimensions of the odor space is also discussed. It is hoped that this type of research will lead to a better understanding of the underlying dimensions used to describe odorants.