Total synthesis of (+/ − )-4-demethylenglerin A

Racemic 4-demethylenglerin A (1′), a simplified analog of the guaiane-type sesquiterpene englerin A (1), has been synthesized. The cyclic hydrocarbon core structure was built through modified Metz approach using epoxynitrile cyclization and direct Aldol reaction to prepare the precursor of RCM. The primary cytotoxicity test summarized that C4 methyl has marked impacts on the bioactivity.     

Effects of tetrahydroxystilbene - glucoside on Animal Models of Dementia or Brain Aging

Aim: To investigate the effects of 2, 3, 5, 4‘-tetrahydroxystilbene-2-O-β-D-glucoside(TSG) from a Chinese Medicinal Herb polygonum multiflorum on dementia or brain aging. Methods. The brain aging model of mice was developed by s. c. injection of D-galactose (50mg/kg/day) for 60 days. The Alzheimer disease (AD) model of mice     

Isolation and Characterization of a Monomethioninesulfoxide Variant of Interferon α-2b

Purpose. To isolate and characterize a monomethioninesulfoxide variant of the commercially available therapeutic protein interferon -2b. Methods. The methionine (Met)-oxidized variant was isolated by reverse-phase high performance liquid chromatography and characterized by SDS-PAGE, peptide mapping and mass spectrometric analysis of the trypsin/V8-generated peptide fragments. The biological and immunological activities of the isolated variant were also evaluated. Results. The rHuIFN -2b variant was found to contain a Met sulfoxide residue at position 111 of the rHuIFN -2b molecule. The far-UV CD spectra showed a slight loss of -helical content and an increase in the -sheet contribution. The CD spectra indicate that both chromatographic conditions and Met oxidation contribute to the observed secondary structure changes. Both interferon -2b main component and its methionine-oxidized variant showed different reactivity to monoclonal antibodies employed in immunoassays for the protein. Conclusions. A monomethioninesulfoxide rHuIFN -2b variant was found to be present in the rHuIFN -2b bulk drug substance in solution. The Met¹¹¹ residue was identified as Met sulfoxide by comparative tryptic/V8 mapping and mass spectrometric analysis. Nevertheless, the oxidation of the Met¹¹¹ residue did not seem to have a detectable effect on the biological activity of the molecule.     

Synthesis and Biological Activities of Some Mannich Bases of 5-(4-Hydroxyphenyl)-1,3,4-Oxadiazole-2-Thione

以对羟基苯甲酸乙酯为原料，经肼解、环化合成５（４羟基苯基）１，３，４二唑２硫酮，继而经Ｍａｎｎｉｃｈ反应合成了四种新曼尼希碱，其结构经红外光谱、核磁共振和元素分析证实。初步抑菌活性试验表明，显示弱的抑菌活性。     

Synthesis and Pharmacokinetics of 2-(4-amino-3,5-dichlorophenyl)-2-(alkylamino)ethanols - Structural Isomers of β2 Agonists Clenproperol and Clenpenterol

Pharmaceutical Chemistry Journal - Methods for the synthesis of 2-(4-amino-3,5-dichlorophenyl)-2-(isopropylamino)ethanol and 2-(4-amino-3,5-dichlorophenyl)-2-(tert-amylamino)ethanol, which are...     

Inclusion complexation of glisentide with α-, β- and γ-cyclodextrins

Complexation of glisentide with α-, β- and γ-cyclodextrin (CD) has been investigated in aqueous solution and in the solid state. Complex formation in solution has been analysed using solubility diagrams and NMR spectroscopy and the interaction in solid state has been studied by X-ray diffractometry, DSC and IR spectroscopy. The thermodynamic parameters, ΔH°, ΔS° and ΔG°, of complexation with β- and γ-CD have been calculated from the temperature dependence of the stability constant. The process has been found to be exothermic and ΔS° is slightly unfavourable. In addition, it has been found that the ionization state of glisentide plays an important role in complexation and the fact that the extent of complexation is greater with β- than with γ-CD has revealed the importance of the cavity size to get an adequate fitting between host and guest molecules. The inclusion of the ortho-substituted aromatic ring of glisentide has been evidenced by NMR spectroscopy. Finally, complexes have been prepared by coprecipitation and kneading methods and it has been found that the former is more suitable to achieve solid-state complexation.     

Relationship of metabolism of 2′-, 3′- and 5′-adenine nucleotides to presynaptic inhibition of transmitter release in rat vas deferens

Summary In the isolated rat vas deferens stimulated at 0.2 Hz, a series of 2, 3-, and 5-substituted adenine nucleotides all inhibited the twitch responses, their actions being potentiated by the nucleoside transport inhibitors, HNBTGR, NBMPR and dipyridamole.The metabolism of these nucleotides was examined utilising HPLC analysis of the bathing medium after exposure to 30 M nucleoside or nucleotide for 5 min. 5-AMP, 5-ADP, 5-ATP, and NAD⁺ were all partially hydrolysed to adenosine, the relative extent of this being 5-AMP>5-ADP=5-ATPNAD⁺. However, the other nucleotides examined were not detectably converted to adenosine or to adenosine deamination products.These results indicate that the 2-, 3- and 5-substituted nucleotides studied act at a P₁-purinoceptor in rat vas deferens to inhibit neurotransmission and, with the exception of 5-AMP, 5-ADP, 5-ATP and NAD⁺, all appear to act directly at this receptor. However, the 5-adenine nucleotides (AMP, ADP and ATP) and NAD⁺ all appear to act at least partially indirectly subsequent to their hydrolysis to adenosine.Abbreviations. The following abbreviations are used ADA adenosine deaminase (EC 3.5.4.4) - 5-ADP adenosine 5-diphosphate - 2,5-ADP adenosine 2,5-diphosphate - 3 5-ADP, adenosine 3,5-diphosphate - 2-, 3 or 5-AMP adenosine 2-, 3-, or 5-monophosphate - 5-ATP adenosine 5-triphosphate - cNADP⁺ -nicotinamide dinucleotide 2,3-cyclic monophosphate - CoA coenzyme A - HNBTGR 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine - NAD⁺ -nicotinamide adenine dinucleotide - NADP⁺ -nicotinamide adenine dinucleotide phosphate - NBMPR 6-(4-nitrobenzylthio)-purine riboside     

Biodistribution and brain permeability of the extracellular domain of neuregulin-1-β1

Neuregulin-1 (NRG1) belongs to a large family of growth and differentiation factors with a key role in the development and maintenance of the brain. Genetic association of NRG1 within brain disorders such as Alzheimer’s disease, schizophrenia and neuroprotective properties of certain NRG1 isoforms have led to a variety of studies in corresponding disease models. In the present work, we investigated NRG1 with regard to its peripheral and central biodistribution after systemic application.We first-time radiolabeled the entire biologically active extracellular domain of NRG1 isotype-β1 (NRG1-β1 ECD; aa 2–246) with iodine-125 and administered it peripherally to healthy adult C57Bl6 mice. Blood kinetics and relative organ distribution of ¹²⁵I-labeled NRG1-β1 ECD were determined. The blood level of NRG1-β1 ECD peaked within the first hour after intraperitoneal (i.p.) application. The brain-blood ratios of ¹²⁵I-labeled NRG1-β1 ECD were time-dependently 150–370% higher compared to the brain impermeable control, ¹³¹I-labeled bovine serum albumin. Autoradiographs of brain slices demonstrated that ¹²⁵I-labeled NRG1-β1 ECD accumulated in several regions of the brain e.g. frontal cortex, striatum and ventral midbrain containing the substantia nigra. In addition we found histochemical and biochemical evidence that phosphorylation of the NRG1 prototype receptor ErbB4 was increased in these regions after systemic application of NRG1-β1 ECD.Our data suggest that NRG1-β1 ECD passes the blood–brain barrier and activates cerebral ErbB4 receptors.     

Lipoic acid - the drug of the future?

Numerous experimental and clinical studies proved efficiency of treatment with lipoic acid-containing drugs in diseases, in which pro- and antioxidant balance is disrupted (diabetes, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), tumors, etc.). Efficiency of lipoate has been attributed to unique antioxidant properties of lipoate/dihydrolipoate system, its reactive oxygen species (ROS) scavenging ability and significant effect on the tissue concentrations of reduced forms of other antioxidants, including one of the most powerful, glutathione (thus lipoate is called an antioxidant of antioxidants). Moreover, analysis of literature data suggests participation of lipoic acid in processes of cell growth and differentiation. This fact can be crucial to clinical practice, however, this problem requires further studies.     

Discovery and characterization of ß-1,6-glucan inhibitors

Importance of the field: The increasing number of patient populations at high risk of opportunistic infections has highlighted the need for the improvement in antifungal treatments. Due to the limited number of currently available antifungal drugs and the concerns for possible prevalence of resistant strains, drugs with a new mechanism of action are most desirable.

Areas covered in this review: Although the cell wall is considered to be one of the ideal targets for antifungal drugs, insufficient information on the enzymes involved in its construction has restricted the discovery of new inhibitors. This review introduces the recent discovery of the inhibitors of β-1,6-glucan, one of the essential components of the yeast cell wall.

What the reader will gain: The readers will gain the strategy to obtain the β-1,6-glucan synthesis inhibitors, their mechanisms of actions, and antifungal activities in vitro as well as in vivo.

Take home message: The β-1,6-glucan inhibitors are considered to be promising candidates for new antifungal drugs which could give valuable options in a clinical setting, although their usage may be limited because of their fungistatic action and limited spectrum. Additionally, they can be useful tools in the study on β-1,6-glucan synthesis and the virulence of Candida species.     

Duration of cannabis use - a novel phenotype?

Although cannabis is the most commonly used illicit drug, duration of cannabis use is typically short, with many of those who initiate cannabis use ceasing use by their late twenties. In this paper we analyze data from a volunteer Australian cohort of 6265 male and female twins to examine whether the duration of cannabis use is an informative phenotype for future genetic analyses. Genetic modeling indicated: (a) moderate genetic influences on duration of cannabis use in both males (41%; 95% CI=31-51) and females (55%; 95% CI=46-63); (b) strong genetic influences on cannabis dependence in both males (72%, 95% CI=61-81) and females (62%, 95% CI=48-74); (c) no evidence of shared environmental influences on duration of cannabis use or on cannabis dependence in either males or females. Importantly, this model fitting indicated that a substantial component of genetic influences (rg=.90, 95% CI=.77-.99 (males); .70, 95% CI=.57-.83 (females)) on duration of cannabis use was shared with those influencing liability to cannabis dependence. While there were high genetic correlations in both women and men, lifetime duration of cannabis may be uniquely informative in assessing components of liability to cannabis use.     

The involvement of μ- and κ- but not δ-opioid receptors in the body weight gain of suckling rats

The effects of the benzomorphan antagonist Mr 2266 and the selective -antagonist ICI 154,129 on the body weight gain of 6-day-old suckling rat pups was observed. Mr 2266 significantly reduced body weight gain in these animals, though ICI 154,129 had no affect on this variable. These findings suggest that - and - but probably not -opioic receptors are involved in the regulation of ingestive behaviours in infant rats. The results are discussed in relation to the development of opioid-receptor subtypes in the neonatal rat brain.     

Discovery and characterization of ß-1,6-glucan inhibitors

Importance of the field: The increasing number of patient populations at high risk of opportunistic infections has highlighted the need for the improvement in antifungal treatments. Due to the limited number of currently available antifungal drugs and the concerns for possible prevalence of resistant strains, drugs with a new mechanism of action are most desirable. Areas covered in this review: Although the cell wall is considered to be one of the ideal targets for antifungal drugs, insufficient information on the enzymes involved in its construction has restricted the discovery of new inhibitors. This review introduces the recent discovery of the inhibitors of β-1,6-glucan, one of the essential components of the yeast cell wall. What the reader will gain: The readers will gain the strategy to obtain the β-1,6-glucan synthesis inhibitors, their mechanisms of actions, and antifungal activities in vitro as well as in vivo. Take home message: The β-1,6-glucan inhibitors are considered to be promising candidates for new antifungal drugs which could give valuable options in a clinical setting, although their usage may be limited because of their fungistatic action and limited spectrum. Additionally, they can be useful tools in the study on β-1,6-glucan synthesis and the virulence of Candida species.     

Association of genes coding for the α-4, α-5, β-2 and β-3 subunits of nicotinic receptors with cigarette smoking and nicotine dependence

We assessed whether smoking behavior was associated with nine polymorphisms in genes coding for the nicotinic receptor subunits α-4 (rs1044394, rs1044396, rs2236196 and rs2273504), α-5 (rs16969968), β-2 (rs2072661 and rs4845378) and β-3 (rs4953 and rs6474413). We conducted an Internet survey and collected saliva by mail for DNA and cotinine analyses, in Switzerland in 2003. We conducted DNA analyses for 277 participants and cotinine analyses for 141 current daily smokers. Cotinine levels were higher in carriers of the CC genotype of CHRNA4 rs1044396 (371 ng/ml) than in those with the CT or TT genotypes (275 ng/ml, p = 0.049), a difference of 0.53 standard deviation units. However, this difference was not robust to correction for multiple testing using Bonferroni adjustment. These 9 polymorphisms were not otherwise associated with smoking behavior and nicotine dependence. There were possible associations between the temperament trait novelty seeking and CHRNA4 rs1044396, CHRNA5 rs16969968 and CHRNB2 rs4845378, but these associations were not robust to correction for multiple testing. We conclude that the analysis of polymorphisms in genes coding for four nicotinic acetylcholine receptor subunits (CHRNA4, CHRNA5, CHRNB2 and CHRNB3) and several smoking-related phenotypes revealed no statistically significant association.     

Kinetics and metabolism of (+)-, (−)- and (±)-bufuralol

Summary Single oral doses of (+)-, (–)- and (±)-bufuralol were administered to a healthy volunteer to compare the disposition and metabolism of the individual isomers and the racemate. Plasma levels and area under plasma curve (AUC) of the active isomer, (–)-bufuralol, were higher than those of the (+)-isomer; plasma clearance was correspondingly lower. Intermediate values were found for the racemate. The elimination half-life of (–)-bufuralol was shorter than that of (+)-bufuralol, but similar to the racemate. Both isomers were cleared almost entirely by metabolism. The main metabolic pathway for (–)-bufuralol was aromatic hydroxylation, whereas the principal route for (+)-bufuralol was conjugation. Phenol metabolites in the systemic circulation were present mainly as conjugates. Both isomers also underwent aliphatic hydroxylation. This pathway was more favoured by the (+)-isomer, although plasma levels and AUC of the principal product, 2-hydroxy-bufuralol, were almost identical for the two forms. Major differences in metabolic fate thus had relatively little effect on the disposition of pharmacologically active metabolites.     

Enhancement of (-)-stepholidine on protein phosphorylation of adopamineand cAMP-regulated phosphoprotein in denervated striatum of oxidopaminelesioned rats

目的：研究左旋千金藤立定（ＳＰＤ）对羟多巴胺损毁大鼠纹状体中ＤＡＲＰＰ３２蛋白磷酸化程度的影响．方法：反磷酸化测定脱磷ＤＡＲＰＰ３２的含量．结果：ＳＰＤ不改变正常大鼠纹状体中ＤＡＲＰＰ３２磷酸化的程度，但能拮抗Ｄ１激动剂的作用；对羟多巴胺损毁大鼠的损侧纹状体，ＳＰＤ使脱磷ＤＡＲＰＰ３２的含量降低４４％，给予Ｄ１拮抗剂可以拮抗这一作用．结论：在损侧纹状体，ＳＰＤ显示Ｄ１激动剂的作用特性，增加ＤＡＲＰＰ３２蛋白的磷酸化，而在正常纹状体，ＳＰＤ表现为Ｄ１拮抗剂．     

Beneficial Effects of （ - ）clausenamide in Experimental Models of Alzheimer＇s Disease

AIMS ： Alzheimer＇s disease （ AD）, which is neuropathologyically characterized by senile plaque composed of amyloid protein depositions,neurofibrillary tangle and neuron loss in central nervous system, is the most common disease occurred in aged people. （ - ） Clausenamide is a new compound isolated from Clausena Lansium Lour Skells, and its natural structure is similar to piracetam. In this study, our aims are to study the （ - ） clausenamide＇s pharmacological effects in various AD＇s pathological models.     

Studies on the action mechanism of the antidepressant effect of [quercetin 3 - O - apiosyl （1→2） ] - rhamnosyl （ 1→6 ） - glucoside

Aim To study the action mechanism of a novel antidepressant [ quercetin 3 -O- apiosyl （1→2） ] - rhamnosyl （1→6） - glucoside（ CTN - 986）, a flavonoid monosomer extracted from cottonseed . Methods （ 1 ） Firstly, using 5 - HTP induced head - twitches model and a special 5 - HT1A receptor agonist 8 - OH - DPAT induced hypothermia in mice, the antidepressant effect of CTN-986 was observed. （2） With immunohistochemistry method, we observed the effect of CTN-986 on neurogenesis and on the level of brain- derived neurotrophic factor （BDNF） in the dentate gyrus of hippocampus in chronically stressed mice. （3） We isolated and cultured neural progenitor cells from neonatal rat hippocampus, and identified the cells with immunocytochemistry method. By using MTT assay and ^3H-thymidine incorporation assay, the effect of CTN -986 on neural progenitor ceils proliferation was observed.