2,4-二甲氧基苯乙胺类α1-肾上腺素受体拮抗剂的合成、生物活性研究

目的设计合成苯乙胺类α1-肾上腺素受体（α1-AR）拮抗剂,并研究它们对大鼠肛尾肌收缩功能的影响。方法以DDPH为先导化合物设计合成了11个新化合物,以2,6-二甲基苯酚为原料经多步反应得中间体卤代苯氧丙酮,再经还原胺化得目标物。运用大鼠肛尾肌收缩功能实验测定目标物的拮抗活性。结果共合成了11个目的物,其结构经IR、HRMS1、H-NMR确证。结论生物活性测试显示大部分目标化合物均具有一定的α1-AR拮抗活性,化合物Ⅲk拮抗作用和DDPH接近。     

α1受体拮抗剂DDPH模拟代谢物的合成及其降压活性^1

设计并合成了１１个α１受体拮抗剂ＤＤＰＨ模拟代谢物（Ｉ１）～（Ｉ１１）,目的物相应的醚酮（Ⅶ１）～（Ⅶ３）,（Ⅷ）和取代苯乙胺（Ⅲ１）～（Ⅲ３）经缩合、还原及成盐制得,化合物（Ⅶ１）,（Ⅶ２）是以２,６－二甲苯氧丙酮经硝化、还原、重氮化、水本酚得,化合物（Ⅷ）以２－甲苯酚为原料,经羟甲基化并与溴丙酮综合制得,目的物及重要中间体的结构经元素分析、红外光谱、核磁共振谱和质谱确证,目的物的急性降压试验表     

2,4-二甲氧基苯乙胺类α1-肾上腺素受体拮抗剂的合成、生物活性研究

目的设计合成苯乙胺类α1-肾上腺素受体(α1-AR)拮抗剂,并研究它们对大鼠肛尾肌收缩功能的影响。方法以DDPH为先导化合物设计合成了11个新化合物,以2,6-二甲基苯酚为原料经多步反应得中间体卤代苯氧丙酮,再经还原胺化得目标物。运用大鼠肛尾肌收缩功能实验测定目标物的拮抗活性。结果共合成了11个目的物,其结构经IR、HRMS1、H-NMR确证。结论生物活性测试显示大部分目标化合物均具有一定的α1-AR拮抗活性,化合物Ⅲk拮抗作用和DDPH接近。     

α1受体拮抗剂DDPH异位手性碳类似物的合成及降压活性

以苯酚及其类似物（Ⅲ）和２－氯丙酸为原料，经中间体２－取代苯氧丙酰胺（Ⅵ１～９），用Ｚｎ－Ｃｌ２－ＫＢＨ４－ＴＨＦ－Ｃ６Ｈ５ＣＨ３体系还原、再成盐得９个新的ＤＤＰＨ异位手性碳类似物（Ⅱ１～９）．目的物和酰胺中间体的结构均经元素分析、红外光谱、核磁共振谱和质谱确证．大部分目的物的急性降压试验表明都有不同程度的降压活性，其中（Ⅱ２）和（Ⅱ５）尤为明显．     

Attenuation of scopolamine induced deficits in navigational memory performance in rats by bis(7) tacrine, a novel dimeric AChE inhibitor

目的：研究他克林的双体衍生物双（７）他克林对东莨菪碱引起的大鼠记忆障碍的影响．方法：采用大鼠Ｍｏｒｉｓ水迷宫固定平台的程序研究空间记忆．以他克林为对照药．结果：东莨菪碱（０３ｍｇ·ｋｇ－１,ｉｐ）使大鼠到达平台的潜伏期明显长于生理盐水对照组．双（７）他克林（０３５μｍｏｌ·ｋｇ－１,ｉｇ或ｉｐ）和他克林（８５２μｍｏｌ·ｋｇ－１ｉｇ;４２６μｍｏｌ·ｋｇ－１ｉｐ）均可对抗东莨菪碱导致的空间记忆障碍;在灌胃及腹腔注射途径下,双（７）他克林的效价,分别强于他克林２４及１２倍．结论：双（７）他克林明显改善东莨菪碱导致的空间记忆障碍,其作用强于他克林．     

左旋丁基苯酞对低糖氧造成神经元损伤的保护作用

目的探讨新药左旋丁基苯酞（1-NBP）对低糖低氧造成的神经细胞坏死和凋亡的保护作用，并从线粒体和细胞内钙角度对其可能的作用机制进行研究。方法：以低糖低氧造成原代培养神经细胞的损伤模型，采用Hoeehest 33824（Hoe）、Ppropidium iodide（PI）、Fluo-3／AM和Rhodamine-123（Rhod）对细胞进行荧光染色，分别测定不同损伤条件下神经细胞的坏死、凋亡、细胞内游离钙和线粒体膜电位的变化，并对1-NBP的保护作用进行观测。结果原代培养神经元的的坏死和凋亡的发生率在低糖氧处理3h后即出现明显升高，     

新型胆碱酯酶抑制剂双（7）—他克林减弱东莨菪碱引起的大鼠空间记 …

目的 研究他克林的双体衍生物双（７）－他克林对东莨菪碱引起的大鼠记忆障碍的影响。方法 采用大鼠Ｍｏｒｒｉｓ水迷宫固定平台的程序研究空间记忆,以他克林为对照药。结果;东莨菪碱（０．３ｍｇ．ｋｇ＾－１,ｉｐ）使大鼠到达平台的潜伏期明显长于生理盐水对照组,双（７）－他克林（０．３５μｍｏｌ．ｋｇ＾－１,ｉｇ或ｉｐ）和他克林（８．５２μｍｏｌ．ｋｇ＾－１ｉｇ,４．２６μｍｏｌ．ｋｇ＾－１ｉｐ）和他克林（８     

苯并呋咱N—氧化物类和喹喔啉双N—氧化物类化合物的合成…

本文合成了一些苯并呋咱Ｎ－氧化物类（２ａ￣３ｃ）及喹喔啉双Ｎ－氧化物类（３ａ￣３ｅ）化合物，初步探讨了体外乏氧选择性细胞毒及放射增敏作用与化学结构的关系，所合成的化合物中（３ ｃ）具有较显著的体外乏氧选择性细胞毒作用及放射增敏作用。     

丁基苯酞对氯化钾及 N-甲基-D-门冬氨酸诱导的大鼠皮质神经细胞损伤的保护作用

用原代培养大鼠皮质神经细胞的方法，观察ｌ丁基苯酞（ｌＮＢＰ）和ｄ丁基苯酞（ｄＮＢＰ）对ＫＣｌ及Ｎ甲基Ｄ门冬氨酸（ＮＭＤＡ）诱导的大鼠皮质神经细胞损伤的保护作用。结果表明：ｌＮＢＰ和ｄＮＢＰ能剂量依赖性地抑制ＮＭＤＡ诱导的大鼠皮质神经细胞内乳酸脱氢酶的释放，降低细胞死亡率，改善受损细胞的形态；此外ｌＮＢＰ和ｄＮＢＰ还能明显减轻ＫＣｌ诱导的神经细胞损伤。提示：ｌＮＢＰ和ｄＮＢＰ对ＫＣｌ及ＮＭＤＡ诱导的大鼠皮质神经细胞损伤有明显保护作用。     

苯并呋咱N－氧化物类和喹喔啉双N－氧化物类化合物的合成及其乏氧选择性细胞毒作用

本文合成了一些苯并呋咱Ｎ－氧化物类（２ａ～２ｃ）及喹喔啉双Ｎ－氧化物类（３ａ～３ｅ）化合物，初步探讨了体外乏氧选择性细胞毒及放射增敏作用与化学结构的关系。所合成的化合物中（３ｃ）具有较显著的体外乏氧选择性细胞毒作用及放射增敏作用。     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

---

Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.