可逆性胆碱酯酶抑制剂 Ⅱ.二甲氨基甲酸间-(烷氨基)烷硫基苯酯的合成

前文报道了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯(I,X=O)的合成,发现催醒安(I,X=O,n=2,R=CH_3)对临床中麻催醒有较好的效果,是一个结构简单、易于合成、具有中枢作用的可逆性胆碱酯酶抑制剂。但催醒安对中枢胆碱酯酶的抑制作用不够强,为此,我们合成了相应的硫代衍生物(Ⅱ,X=S)(表2)以期能增强对中枢胆碱酯酶的抑制作用。     

可逆性胆碱酯酶抑制剂二甲氨基甲酸-[3-(烷氨基)烷氧基-4(5)-叔丁基]苯酯的合成

在催醒安的邻位和对位异构体及其同系物的苯坏上引入烷基后,可以增强抑制胆碱酯酶的活性,我们乃进一步在催醒安及其同系物的苯环不同位置上引入叔丁基,合成了一系列二甲氨基甲酸-[3-(烷氨基)烷氧基-4(5)-叔丁基]苯酯(Ⅰ_(1～13)和Ⅱ_(1～5))(表2),以探索对活性的影响。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯的合成

前报报道在“催醒安”的对位异构体的苯环上引入烷基,可以增强对胆碱酯酶的抑制作用。为了探索在邻位异构体(Ⅰ)的苯环上引入烷基对生理活性的影响,合成了二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯(Ⅱ)。     

中麻催醒剂——Ⅰ.二甲氨基甲酸间-(烷氨基)烷氧基苯酯的合成

合成了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯,并进行了实验动物的毒性和中麻催醒试验。初步临床观察表明,化合物Ⅱ_4(现命名为催醒安)比毒扁豆碱的催醒效果好,而毒性小。简要地讨论了结构和生物活性之间的关系。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-5-(1,3,3-三甲基-6-取代基)吲哚满酯的合成

催醒宁(I,R=H,R′X=HCl)对胆碱酯酶的抑制作用较强,但稳定性较差,作用时间较短。推测可能与其酯基易于水解有关。鉴于催醒宁结构中的氨基甲酸酯是抑酶作用的药效基团,酯基被水解后,抑酶活性即消失,我们设想,如果在催醒宁结构中的酯基邻位上引入取代基,利用其空间效应的影响,使酯基增加对水解的稳定性,或有可能达到延长作用时间的目的。因此,我们合成了二甲氨基甲酸-5-(1,3,3-三甲基-6-取代基)吲哚满酯盐酸盐和季铵盐(Ⅰ_(1～14),表1),以探索取代基对抑酶强度和作用时间的影响。     

中麻催醒剂——Ⅰ.二甲氨基甲酸间-(烷氨基)烷氧基苯酯的合成

合成了一系列二甲氨基甲酸间-(烷氨基)烷氧基苯酯,并进行了实验动物的毒性和中麻催醒试验。初步临床观察表明,化合物Ⅱ₄(现命名为催醒安)比毒扁豆碱的催醒效果好,而毒性小。简要地讨论了结构和生物活性之间的关系。     

催醒安在大鼠尿内代谢产物的研究

催醒安是一种新的中枢性抗胆碱酯酶药。给大鼠灌胃后,用HPLC分离纯化尿提取液中的代谢产物,得到四个组分。经MS鉴定分别为原形药物,N-羟甲基,N-甲基氨基甲酸-[间-(2-二甲氨基)]乙氧基苯酯(简称羟基化催醒安),N-甲基氨基甲酸-[间-(2-二甲氨基)乙氧基]苯酯(去甲基催醒安)及间-(2-二甲氨基)乙氧基苯酚(催醒安水解物)。原药及产物对电鳐乙酰胆碱酯酶抑制率的实验表明,去甲基催醒安抑酶活性与原药相近,羟基化催醒安活性比原药低,水解物无抑酶活性。     

4-硝基二苯醚-4′-硫代氨基甲酰胺类化合物的合成及其抗日本血吸虫作用

我们在改造硝硫氰胺(Ⅰ)的结构、寻找高效低毒的抗日本血吸虫病药物时,发现某些4-硝基二苯胺-4′-硫代氨基甲酸的衍生物,例如芳酯(Ⅱ)具有较强的抗日本血吸虫作用,其中4-硝基二苯胺-4′-氨基硫代甲酸(O)苯酯(硝硫苯酯,Phenithionate)的疗效与I相同,但毒性明显降低,已作为治疗日本血吸虫病新药,在临床试用。鉴于4-硝基-4′     

硝硫苯酯及其有关硫代氨基甲酸衍生物的合成和抗日本血吸虫作用

本文报道22个4-硝基二苯胺-4′-硫代氨基甲酸衍生物和其二苯醚二苯硫醚类似物的合成,大多数化合物为氨基甲(?)酸芳酯。筛选结果表明4-硝基二苯胺-4′-氨基甲(?)酸芳酯和二苯醚类似物有较强的抗日本血吸虫作用而二苯硫醚类似物则无明显的抗虫作用。4-硝基二苯胺-4′-氨基甲(?)酸苯酯——硝硫苯酯(代号7720)已作为抗日本血吸虫病药物在临床试用,证明其疗效较高,毒性较低。本文还简要讨论了结构和抗日本血吸虫作用的关系。     

(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究

目的　制备(6R,7R) - 7-[2 -呋喃基(甲氧亚氨基)乙酰氨基] - 3-羟甲基- 8-氧代- 5 -硫杂- 1-氮杂二环[4 2 0]辛- 2 -烯- 2 -甲酸。方法　通过7-氨基头孢烷酸的水解,生成去乙酰基7-氨基头孢烷酸,再与2 - (2 -呋喃基)- 2 -甲氧亚胺基乙酸氯反应进行7位氨基的酰化制备上述医药中间体。结果及结论　适宜的反应条件为:7-氨基头孢烷酸在- 2 5℃水解,与2 - (2 -呋喃基) - 2 -甲氧亚胺基乙酰氯在- 10℃反应,二者的摩尔比为1 0∶1. 15,收率可达80 %。     

Effect of metabolism on the anticholinesterase activity of parathion and paraoxon in primary neuron cultures

The anticholinesterase activity of parathion and paraoxon, and the effects of metabolism on this activity, were examined in primary cultures of chick embryo forebrain neurons. Paraoxon was an extremely potent inhibitor of acetylcholinesterase activity, with a median inhibitory concentration (IC₅₀) more than 800 times more potent than parathion. Incubation of these two compounds with rat hepatic S-9 fractions, before neuron treatment, dramatically altered their activity, though with opposite effects. Parathion, when preincubated with control S-9 (from saline-treated rats), exhibited increased anticholinesterase activity, whereas paraoxon was much decreased in potency. The relative anticholinesterase activity of these compounds after incubation with the control S-9 fractions was much more predictive of the relative toxicites of these compounds in vivo. Preincubation of these compounds with hepatic S-9 fractions that had been obtained from rats induced with either phenobarbitone or 3-methylcholanthrene, resulted in a decreased activation of parathion and an increased deactivation of paraoxon compared with control S-9.     

Anticholinesterase activity of elapid venoms

Of 16 elapid venoms from Naja, Bungarus, Ophiophagus, Dendroaspis, Hemachatus and Notechis species, only Notechis scutatus venom totally lacked anticholinesterase activity while N. nigricollis, M. fulvius, D. jamesoni, D. polylepis and D. angusticeps lacked acetylcholinesterase activity. Zinc ions were necessary for anticholinesterase activity; cobaltous ions being less effective in restoring anticholinesterase activity, while magnesium, nickelous, stannous and manganous ions were inactive. Notechis scutatus and to a lesser extent Dendroaspis jamesoni venom enhanced the acetylcholinesterase activity of Bungarus fasciatus venom when incubated together in the presence of zinc.     

夏天无总碱中抗胆碱酯酶活性成分的研究

夏天无为罂粟科植物伏生紫堇Ｃｏｒｙｄａｌｉｓｄｅｃｕｍｂｅｎｓ (Ｔｈｕｎｂ .)Ｐｅｒｓ .的干燥块茎 ,是我国常用中草药 ,有活血通络、行气止痛之功效 ,用于中风偏瘫、跌打损伤、风湿性关节炎和坐骨神经痛等[1,2 ] ,现代药学研究认为其主要有效部位为生物碱[2 ,3 ] 。在对夏天无总生物碱的研究中 ,作者发现其有较强的抑制乙酰胆碱酯酶 (ａｃｅｔｙｌｃｈｏｌｉｎｅｓｔｅｒａｓｅ ,ＡＣｈＥ)活性的作用 ,该作用未见报道。本文采用色谱法对夏天无总生物碱进行了成分分离 ,得到 5个化合物 ,经结构鉴定为 :四氢掌叶防己碱 (Ｉ)、原阿片碱 …     

Effect of oximes on the acute toxicity of anticholinesterase carbamates

The acute toxicities of eight anticholinesterase carbamates were determined in male rats by sc injection, both in the absence and in the presence of therapeutically administered atropine sulfate or pyridinium oximes. Atropine reduced the toxicities of all carbamates, and the oximes obidoxime and P2S, when used in combination with atropine, generally enhanced the therapeutic efficiency of atropine. When used alone, the oximes also reduced the toxicity of carbamates by varying degrees. However, an exception was seen in the case of carbaryl. Here, the therapeutic administration of oximes markedly increased the toxicity, and when used in combination with atropine, obidoxime markedly reduced the protection afforded by the alkaloid. The influence of obidoxime and P2S on the inhibition of cholinesterase in vitro by the carbamates was measured, and it was found that they influenced the anticholinesterase activity of the carbamates in a pattern similar to their effect on the toxicity of the carbamates. It is concluded that a causal relationship exists between the toxicity of carbamates and factors affecting their anticholinesterase activity. The increased toxicity and the anticholinesterase activity of carbaryl in the presence of the oximes are unique to this carbamate among those studied.     

Paraoxon increases the rate of synthesis of acetylcholinesterase in cultured muscle

Acetylcholinesterase (AChE) activity of cultured chick embryonic pectoral muscle was significantly increased above control activity during recovery from brief treatments with paraoxon (O, O-diethyl-p-nitrophenyl phosphate), the anticholinesterase metabolite of parathion. Paraoxon also increased the rate of degradation of the enzyme, suggesting the higher AChE activity of paraoxon-treated cells was due to a stimulation of enzyme synthesis.     

Intoxication with huperzine A, a potent anticholinesterase found in the fir club moss

BACKGROUND: Herbs from Lycopodium are generally reputed to be nontoxic and are occasionally used for preparing a salubrious tea. In Europe, the common Lycopodium clavatum can be easily confused with Lycopodium selago, the fir club moss. CASE REPORT: We report 2 patients who drank a tea, erroneously prepared from dried herbs of Lycopodium selago, which resulted in sweating, vomiting, diarrhea, dizziness, cramps, and slurred speech. These symptoms were suggestive of a cholinergic mechanism. To elucidate the active principle, aqueous extracts of Lycopodium selago were checked for their suspected anticholinesterase activity using human erythrocytes as an enzyme source in a modified Ellman assay. The extracts did exhibit significant anticholinesterase activity. The anticholinesterase(s) were most effectively extracted with dichloromethane and isolated by high-performance liquid chromatography. The major compound with anticholinesterase activity co-chromatographed with authentic huperzine A, but had a 2-3-fold higher inhibitory potency than the racemic standard. The amount of huperzine A found in the Lycopodium selago sample used for the tea preparation was calculated to be sufficient for a relevant acetylcholinesterase inhibition. CONCLUSION: The signs and symptoms of Lycopodium selago poisoning are consistent with the anticholinesterase activity of huperzine A and should favorably respond to atropine therapy. This report demonstrates once more that laymen should not be encouraged to gather their remedies from "Mother Nature" without advanced botanical knowledge.     

In vitro effects of soman on bronchial smooth muscle

The in vitro exposure of rat bronchial smooth muscle to the cholinesterase inhibitor soman (O-[1,2,2-trimethylpropyl]-methyl-phosphonofluoridate) potentiated the rapid and concentration dependent increase in the contraction induced by acetylcholine (ACh). There was a substantial increase in the response to ACh when soman was present in concentrations from 10 nM to 1 microM which correspond to a 65-100% inhibition of acetylcholinesterase (AChE). The apparent affinity (pD2) to ACh increased from 3.7 to 6.7 without any change in intrinsic activity (alpha) in this concentration interval. In contrast, soman did not alter the apparent affinity or intrinsic activity of carbachol, which supports the suggestion that the effect of soman is entirely due to its anticholinesterase activity. Soman by itself induced contraction which begun at 1-10 nM. This may be explained from its anticholinesterase activity and the subsequent increase in the synaptic concentration of spontaneously released ACh. The effect of soman on inhibition of cholinesterase and carboxylesterases have also been examined. The results demonstrate that low concentrations of soman induces contraction of the airway smooth muscle.     

The in vitro inhibitory effect of psilocybin and related compounds on human cholinesterases

Summary The comparison of the anticholinesterase activity of psilocybin, bufotenin and 5-hydroxytryptamine in human plasma, red cells and gray matter homogenate indicates that like with LSD and its derivatives, there is no correlation between the in vitro anticholinesterase activity and the hallucinogenic effect of these compounds. This investigation was supported by U.S.P.H. Grant No. M-1425 (C3) and Grant No. E-59 1960 of the Health Research and Services Foundation of Pittsburgh, Pa.