氚标记( )与(-)棉酚在大鼠主要脏器的亚细胞分布及共价结合

给大鼠腹腔及睾内注射氚标记的( )与(-)棉酚后第7、18天,对主要脏器中各亚细胞组分的总放射活性及共价结合的放射活性进行了动态观察。结果表明,(-)棉酚在心肌线粒体共价结合放射活性较明显高于( )棉酚;( )及(-)棉酚在睾丸细胞膜、微粒体共价结合的放射活性随时间增高,且(-)棉酚较为明显。     

消旋棉酚拆分的研究——Ⅱ.手性α-甲基苯乙胺及α-甲基苄胺为拆分剂

本文报道用中压柱色谱快速分离S或R-α-甲基苯乙胺及S或R-α-甲基苄胺缩(±)-棉酚的方法,可得光学活性胺缩(+)或(一)-棉酚非对映体,经水解分别得到(+)或(一)-棉酚。并证明胺缩光学活性棉酚非对映体之间有互相转化的性质,此特性可利用于棉酚对映体的转化。     

从天然植物制取(一)棉酚

本文首次报道从天然植物——海岛棉籽中分离出(-)棉酚。同时发现了受试的各种棉籽所含棉酚的光学活性的规律。(1)棉籽中棉酚的两个对映体(-)棉酚和(+)棉酚一般是不等量的,故其成分应为(±)棉酚和过量的(-)棉酚或(+)棉酚;(2)同种属棉籽含有相同旋光性的过量对映体,如海岛棉籽均含有过量的(-)棉酚,多数品种所含棉酚的光学纯度为10～25%,陆地棉籽则均含有过量的(+)棉酚,其相应棉酚的光学纯度为10～20%。     

(-)棉酚和(+)棉酚对蛋白激酶C及蛋白激酶A活力影响的比较

部分纯化的大鼠肝脏蛋白激酶C和蛋白激酶A,在体外与棉酚的旋光异构体分别温育,结果(--)棉酚和(+)棉酚对蛋白激酶C活力均有剂量依赖性的抑制作用;(-)棉酚对Ⅰ型蛋白激酶A活力的抑制作用明显比(+)棉酚强,而(-)棉酚和(+)棉酚在高浓度时对Ⅱ型蛋白激酶A才显示抑制作用。结果提示棉酚在体内可能干扰细胞信息的传递过程。     

消旋棉酚晶态结构的研究

目的:研究消旋棉酚晶形结构。方法:采用红外光谱(IR)、差示扫描量热法(DSC)、测定溶解度和粉末X射线衍射法(XRD)来研究消旋棉酚晶态结构。结果:消旋棉酚[(±)G]、左旋棉酚[(-)G]和右旋棉酚[(+)G]的红外谱图基本相同;DSC图谱及热特征数据不一致;在消旋棉酚的饱和溶液中加入光学活性棉酚,光学活性棉酚可以继续溶解,并且有旋光产生;(±)G与(-)G及(+)G的XRD图完全不同。结论:消旋棉酚晶体属于外消旋化合物。     

(-)和(+)棉酚对雄大鼠生育力的影响

棉酚有明显的抗雄性生育作用,但在理论上尚不清楚消旋棉酚的抗生育作用和毒性来自那一种光学异构体。已有报告指出(+)棉酚无毒无效。但对(-)棉酚的研究迄今尚未有报道。本文应用本所合成室制备之(+)和(-)棉酚,观察了他们的抗生育作用。实验用Wistar雄大鼠(190～220g)25只,分为对照,(+)棉酚30mg/kg,(-)棉酚15和30 mg/kg以及消旋棉酚30 mg/kg等5组。每天喂药1次,(+)棉酚和(-)棉酚     

消旋棉酚拆分的研究——Ⅳ.苏(-)或(+)-1-(对硝基苯基)-1,3-二羟基丙胺-2为拆分剂

本文介绍以光学活性苏-1-(对硝基苯基)-1,3-二羟基丙胺-2为拆分剂,与消旋棉酚缩合,用常压柱色谱或溶剂结晶法分离得到两个光学纯的非对映体,然后分别水解得(+)和(-)-棉酚。     

消旋棉酚拆分的研究——Ⅱ.手性α-甲基苯乙胺及α-甲基苄胺为拆分剂

本文报道用中压柱色谱快速分离S或R-α-甲基苯乙胺及S或R-α-甲基苄胺缩(±)-棉酚的方法,可得光学活性胺缩( )或(一)-棉酚非对映体,经水解分别得到( )或(一)-棉酚。并证明胺缩光学活性棉酚非对映体之间有互相转化的性质,此特性可利用于棉酚对映体的转化。     

棉酚对大鼠胆汁谷胱甘肽含量的影响

<正> de Peyster等证明棉酚与大鼠肝微粒体及人精子体外温育能产生自由基,推测可能是棉酚生物活性的基础。新近报道右旋(+)及左旋(-)棉酚(gossypol,G)体外与大鼠肝及肾微粒体温育能产生自由基。但自由基的生成是否为棉酚抗生育以及血清谷丙转氨酶(ALT)升高的毒性机理,值得进一步探讨。     

14C-棉酚:棉花幼苗生物合成的最佳条件(英文)

将[1-¹⁴C]-乙酸钠加入棉花(Gossypium hirsutum c.v.ST-506)幼苗的培养液中,经四天的培育,得到最高放射活性的棉酚。实验中亦显示体外加乙酸钠具有激发棉酚生物合成的特性。每两百株棉花幼苗加入6 mg乙酸钠可得最高量的棉酚。     

3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine.

The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives (+/-)fenfluramine, (+/-)norfenfluramine, (+/-)MDE, (+/-)PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.     

Turnover of 3H-5-hydroxytryptamine to 3H-5-hydroxyindoleacetic acid and the 3H-5-methoxyindoles in nondeprived and 24 hr food deprived rats.

Serotonin turnover in the lateral in hypothalamus (LH) was determined in nondeprived and 24 hr food deprived rats. The LH was infused with 0.5 muCi of 3H-5-hydroxytrptamine 1 hr prior to push-pull perfusion. The percentage of nCi/muCi of radioactivity was analyzed by thin layer chromatography and liquid scintillation spectrometry. There was significantly more 5-hydroxyindoleacetic acid and 5-methoxytryptamine formed in the 24 hr food deprived rats. These results indicate a faster 5-hydroxytryptamine turnover rate in the LH of 24 hr food deprived rats than in nondeprived rats.     

靛玉红及其乙基和十八烷基衍生物在动物体内命运的比较

N₁′-乙基靛玉红(79002)对动物移植性肿瘤的抗癌活性优于靛玉红;而N₁′-十八烷基靛玉红(79005)则较靛玉红差。本文比较了³H-靛玉红及³H-79002和³H-79005在小鼠及大鼠的体内命运。结果表明,³H-79002吸收最易,瘤内放射性最高,组织内存留时间较长;而³H-79005吸收最难,给药后以胃肠分布的放射性最高,组织内存留时间最短。这些结果表明三者体内过程的差别与其抗癌活性的差别相一致。     

(-)和(+)棉酚对雄大鼠生育力的影响

Racemic, (-) and (+) gossypol, provided by the Department of Organic Chemistry of our institute, was suspended in 2.5% tween 80 solution. Adult male Wistar rats 190～220 g in weight were allotted to 5 groups. Animals in group 1 received 2.5% tween 80 solution as control. Rats in group 2 were treated with racemic gossypol at the dosage of 30 mg/kg for 2 weeks. Animals in group 3 and 4 were given 15 mg/kg of (-) gossypol for 2 weeks and 30 mg/kg of (-) gossypol for 1 week respectively. Rats in group 5 were treated with (+) gossypol at the dosage of 30 mg/kg for 2 weeks.Four weeks from the beginning of gossypol treatment the rats were cohabited with adult females for 7 days. Then the motility of the sperms in the cauda epididymides was estimated The female rats were examined for pregnancy 7 days later.Treatment with (-) gossypol at 30 mg/kg caused significant decreases in body weight of the rats (P<0.05). One of the five rats died 7 days after the last administration, while (+) gossypol and racemic gossypol at the dosage employed had no effect on the body weight. (+) Gossypol at 30 mg/kg for 2 weeks had no effect on the motility of the sperms in the cauda epididymides and no effect on the fertility of the animals: nor was there any effect on the weights of the testis, epididymis, prostate and seminal vesicle. The sperms of the cauda epididymides were found to be dead in the groups treated with 15 and 30 mg/kg of (-)gossypol. Raccmic gossypol given for 2 weeks at 30 mg/kg caused loss of fertility of the male rats which confirmed our previous findings.(?)t may be postulated that (+) gossypol has no antifertility effect nor toxicity at the dosage employed. (-) Gossypol is the active stereoisomer of racemic gossypol.     

Metabolism and distribution of 14C- and 35S-labeled carbon disulfide in immature rats of different ages

The metabolism and distribution of 14C- and 35S-CS2 was examined in 1-, 5-, 10-, 20-, 30-, and 40-day-old rats. During a 3-hr period following an ip dose of 14C-CS2, 58-83% of the dose was expired as CS2 and 4-9% was metabolized to expired CO2 depending on age. Thirty- and forty-day-old rats metabolized significantly more CS2 to CO2 and expired significantly less CS2 than 1- through 20-day-old rats. At the end of the measured expiration period, only biotransformation products of CS2, which were in part covalently bound, remained in tissues from rats of all ages. Tissue levels of 35S-CS2-derived radioactivity exceeded levels of 14C-CS2-derived radioactivity indicating that sulfur metabolites free from the carbon atom of CS2 were formed in rats as young as 1 day of age. The 35S-CS2-derived radioactivity per g of tissue and thus 35S covalently bound to tissue protein was significantly higher in 1- through 20-day-old rats than in 30- and 40-day-old rats. Twenty-four hr after dosing, up to 13 times more 35S-labeled metabolites were covalently bound in organs from 1-day-old rats than in similar organs from 40-day-old rats. The results showed that elimination of the biotransformation products of CS2, in particular the covalently binding sulfur metabolites, was prolonged in newborn rats in comparison to 40-day-old rats.     

Binding of the potent allergen hexahydrophthalic anhydride in the mucosa of the upper respiratory and alimentary tract following single inhalation exposures in guinea pigs and rats.

Hexahydrophthalic anhydride (HHPA; CAS No. 13149-00-3) is a highly allergenic compound commonly used in the chemical industry. Guinea pigs and rats were exposed to [3H2]HHPA by inhalation for 3-8 h and were killed at various intervals during 7 days. The tissue distribution of non-volatile and covalently bound radioactivity was studied by autoradiography. Tissue bound radioactivity was mainly found in the mucosa of the upper respiratory airways, whereas negligible levels were observed in the lungs. In addition, tissue bound radioactivity was present in the gastrointestinal tract and conjunctiva. Moreover, in the cortex of the kidneys in rats, but not in guinea pigs, a low level of tissue bound radioactivity was found. The radioactivity in the tissues persisted for at least 7 days after the end of exposure. Plasma proteins and soluble proteins from trachea, lung, and kidney from [3H2]HHPA-exposed animals were separated by gel filtration. The radioactivity in dialysed plasma was mainly found in the same fractions as albumin. The soluble proteins from trachea, lung, and kidney in both rats and guinea pigs showed a similar pattern as found in blood. The radioactivity in dialysed plasma from both guinea pigs and rats seemed to decay according to a two-compartment model. The non-extractable binding of [3H2]HHPA in the upper respiratory airways and conjunctiva may be of relevance for symptoms in workers with allergy, since they mainly develop symptoms and signs from the nose and eyes.     

Metabolism, pharmacokinetics, and protein covalent binding of radiolabeled MaxiPost (BMS-204352) in humans.

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of (14)C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg (14)C-labeled BMS-204352 (50 microCi) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t(1/2) of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of (14)C-labeled BMS-204352 were observed in humans, dogs, and rats.     

Lack of a role for cardiac sympathetic nerves in the uptake and metabolism of 3H-5-hydroxytryptamine by isolated rabbit hearts.

Perfused rabbit hearts removed 3H-5-hydroxytryptamine (3H-5-HT) from a perfusion solution containing 2.6 ng/ml and a tissue-to-medium ratio of about 10 was achieved after a 55 min perfusion period. 12.4 +/- 1.0% of the cardiac total radioactivity consisted of metabolites and metabolites appeared in the venous effluent during the course of the perfusion. Pretreatment of animals with 6-hydroxydopamine reduced cardiac noradrenaline concentrations by 92%, abolished the histochemical fluorescence characteristic of noradrenaline in sympathetic nerves and abolished the mechanical response to sympathetic nerve stimulation. In these hearts, the removal of 3H-5-HT from the perfusion fluid and the accumulation of total radioactivity was normal. There was, however, a significant increase in the proportion of the total cardiac radioactivity which was present as metabolites. The results suggest that the cardiac sympathetic nerves are not the site of 3H-5-HT uptake when the concentration in the perfusion medium is low. By analogy with work in the lung, it may be the endothelial cells of the coronary microcirculation which are responsible.     

Synthesis and calcium antagonistic activities of fecal metabolites of a new calcium antagonist (+)-(R)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N- [2-[(3,4-methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4- methyl-3-oxo-2H-1,4-benzothiazine (SD-3211) in rats

In order to confirm the structure of three fecal metabolites, M-I, M-II and M-III, of a new calcium antagonist, (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4- benzothiazine (SD-3211), in rats, (+)-3,4-dihydro-2-[5-hydroxy-2-[3-[N-methyl-N-[2- [(3,4-methylenedioxy)-phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl- 3-oxo-2H-1,4-benzothiazine((+)-I), (+)-3,4-dihydro-2-[5-hydroxy-2-[3-[N- [2-[(3,4-methylenedioxy) phenoxy]ethyl]amino] propoxy]-phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine((+)-II) and (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-[2-[(3,4-methylenedioxy) phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4- benzothiazine((+)-III) were synthesized. Compounds (+)-I, (+)-II and (+)-III were identified with the fecal metabolites M-I, M-II and M-III, respectively. The calcium antagonistic activities of (+)-I, (+)-II and (+)-III were examined.