卤代苄基异喹啉类化合物的合成

卤代苄基异喹啉类化合物的合成伍家泉，陈虹，王火，庞开圻，陈琪瑞（开平彼迪药业有限公司，开平５２９３３１）（天津武警医学院，天津３００１６２）苄基异喹啉类生物碱广泛存在于天然植物中，其中许多具有重要的生理活性，尤其在心血管方面的作用引人注目。曾证明唐松...     

蝙蝠葛中一新双苄基异喹啉生物碱

防己科植物蝙蝠葛（ＭｅｎｉｓｐｅｒｍｕｍｄａｕｒｉｃｕｍＤＣ．）根茎中的脂溶性酚性生物碱具有抗多种实验性心律失常活性〔１〕,近年研究表明,其主成分蝙蝠葛碱（ｄａｕｒｉｃｉｎｅ,１）和蝙蝠葛苏林碱（ｄａｕｒｉｓｏｌｉｎｅ,２）延长心肌动作电位时呈使用...     

双苄基异喹啉类生物碱的生物活性与构效关系

综述了双苄基异喹啉类生物碱的生物活性和构效关系。     

N—取代四氢苄基异喹啉类化合物的合成

Ｎ┐取代四氢苄基异喹啉类化合物的合成马玉卓１）刘鹰翔（鱼它滨化学药业总公司研究所，汕头５１５０４１）容士宏张新华（沈阳药科大学制药系，沈阳１１００１５）近来国内文献曾报道一系列苄基异喹啉衍生物或类似物对心血管系统具有多方面的药理作用［１～３］。但是通...     

苄基异喹啉类生物碱药理作用及机制的研究进展

苄基异喹啉类生物碱是自然界中很重要的一类生物碱,数量多,结构类型复杂。药理学研究已经证实苄基异喹啉类生物碱具有抗肿瘤、抗炎、抗病毒以及抗血小板凝集、抗心律失常和抗高血压等心血管疾病的多种药理活性,同时该类生物碱还显示出抗菌、肌肉松弛、降血糖、机体自身免疫调节以及中枢神经系统方面的药理作用,临床应用表明了确实的疗效。本文对该类生物碱丰富的药理作用及机制研究进行了综述。     

轮环藤根中双苄基异喹啉类生物碱的研究

轮环藤Cyclea racemosa Oliv.,四川作为防己药用,名“平昌防己”。从根中获得四种结晶成分,经光谱鉴定,结晶Ⅱ为轮环藤碱(Cycleanine),Ⅲ为海岛轮环藤碱(Insularine),Ⅳ为异粒枝碱(Isochondodendrine)。结晶V结构尚在鉴定中(可能为一新的双苄基异喹啉类生物碱)。本文首次报道了海岛轮环藤碱的~1H和~(13)CNMR谱,并分析讨论了两个芳环(C,C′)的构型。     

双苄基异喹啉类生物碱汉防己乙素的二维核磁共振谱

目的：系统研究汉防己乙素的核磁共振谱。方法：应用1D（^1H,^13C)和2D（^1H-^1HCOSY,HMQC,HMBC)NMR技术,结果：首次指定了汉防己乙素NMR谱中所有^1H(^13C）信号的化学位移。结论：2D NMR技术是解决汉防己乙素^1H(^13C)信号峰归属的关键。     

异喹啉类化合物对心血管作用的研究现状

异喹啉类化合物种类多,天然来源广,有些已经广泛应用于临床,尤其用于心血管疾病,如高血压,心肌缺血和心律失常等,其中包括小檗碱、四氢小檗碱、千金藤碱、四氢巴马丁等,此类化合物有广谱的离子通道有受体作用,可作用于钾、钠、钙通道的α、β、５－羟色胺、多巴胺受体。本文结合对若干具体药物的研究结果就异喹啉类化合物的心血管作用及其机制进行了综述。     

双苄基异喹啉类生物碱粉防己碱与小檗胺逆转多药抗药性的比较研究

比较了2种结构相近的双苄基异喹啉(BBI)生物碱粉防己碱(TTD)、小檗胺(BBM)与维拉帕米(VRP)逆转多药抗药性的作用。结果,TTD,BBM和VRP在多药抗药的MCF-7/Adr和KBv₂₀₀细胞对ADR和VCR均有明显增敏作用,且作用呈剂量依赖性。其中10μmol·L^-1TTD能完全逆转MCF-7/Adr细胞对ADR的抗药性。TTD,BBM和VRP均有增加MCF-7/Adr细胞内阿霉素积累的作用。TTD和BBM在结构上仅有微小差别,但TTD的逆转MDR作用优于VRP10倍,而BBM的作用与VRP相仿。TTD在裸鼠体内MCF-7/Adr实体瘤模型上也证实有明显逆转ADR抗药性的作用。     

和厚朴酚对钙调素拮抗作用的研究

采用钙调素(CaM)依赖性环核苷酸磷酸二酯酶及丹磺酰标记CaM,研究和厚朴酚对CaM的作用.发现和厚朴酚能抑制CaM刺激环核苷酸磷酸二酯酶的活性,随着CaM浓度的增加,IC_(50)也相应增加。在Ca~(2+)存在下.和厚朴酚能降低丹磺酰标记的CaM的荧光强度,使其荧光发射光谱峰位红移。实验结果提示,和厚朴酚在Ca~(2+)存在下,能与CaM结合.从而拮抗其对靶酶——磷酸二酯酶的激活。另外,和厚朴酚对CaM依赖性磷酸二酯酶基础活性具有刺激作用。     

API_（0134）对钙调素及其依赖性环核苷酸磷酸二酯酶的作用

应用钙调素（ＣａＭ）靶酶环核苷酸磷酸二酯酶（ＰＤＥ－Ｉ）活性测定方法观察穿心莲有效成分（ＡＰＩ０１３４）拮抗ＣａＭ的作用。当ＡＰＩ０１３４浓度大于７．８ｍｇ·Ｌ－１时能明显抑制ＣａＭ激活ＰＤＥ－Ｉ的活性，其半抑制浓度（ＩＣ５０）为２６·９ｍｇ·Ｌ－１，在浓度为７．８～１２５ｍｇ·Ｌ－１范围内，ＡＰＩ０１３４对ＰＤＥ－Ｉ的基础活性没有影响。     

Changes in soluble calmodulin following activation of dopamine receptors in rat striatal slices.

Various molecular forms of cyclic nucleotide phosphodiesterase (PDE) are present in the striatum of rats. While Ca²⁺ by itself cannot modulate striatal PDE, this ion is essential for the activation of striatal PDE by calmodulin (CaM). Incubation of striatal slices with apomorphine (10^?7 M) for 30 min increased the total CaM content of the supernatant fraction. Also the amount of CaM associated with PDE was increased and the K_m of PDE for cAMP was lowered. A shorter incubation with dopamine or apomorphine (10 min) failed to increase CaM and to lower the K_m of PDE.Haloperidol (10^?7 M), a dopamine receptor antagonist, prevented the change in the kinetic profile of PDE elicited by dopamine (2 × 10^?7M). Transection of the nigra-striatal fibre bundle by itself did not change the kinetic profile of striatal PDE, but in slices prepared from deafferented striata, a 30 min activation of dopamine receptors still elicited a decrease in the K_m of PDE for cAMP. These findings suggest that following a persistent stimulation of dopamine receptors, the CaM content increases in the cytosol because it is mobilized from a pool located in post-synaptic membranes. This mobilization of CaM regulates PDE; thus, regulation of PDE through a translocation of CaM may participate in reducing the functional output of dopamine receptors following persistent stimulation.     

Intoxication by benzodiazepines: studies with diazepam used as a model compound suggest an interaction with red blood cells calmodulin dependent (CA2+, MG2+) ATpase

20 patients under therapy or intoxicated by benzodiazepines were studied. A partial inhibition of (Ca²⁺, Mg²⁺)ATPase on ‘B’ membranes (CaM rich membranes) was evident in 2 cases. A total inhibition of (Ca²⁺, Mg²⁺) ATPase on both ‘B’ and ‘A’ (CaM depleted) membranes was noted in 1 case: the patient who was severely intoxicated had pronounced hemolysis. As an attempt to elucidate the mechanism of this action, the effect of diazepam chosen as model compound was studied on ‘B’ and ‘A’ membranes prepared from normal human RBC previously incubated with diazepam. A high concentration of diazepam, corresponding to a 20-fold therapeutic level results in a 50% inhibition of the maximal activity of the enzyme on ‘B’ membranes. It may be speculated from these experiments that the effect of high concentration of benzodiazepines on CaM dependent (Ca²⁺, Mg²⁺) ATPase leads to accelerated RBC destruction.     

α－双炔失碳酯对红细胞膜和钙调蛋白功能的影响

探讨α－双炔失碳酯对细胞膜功能的影响．结果表明，α－双炔失碳酯对红细胞溶血有很强的保护作用．１ｍｇ·Ｌ－１时保护率达７０％。该作用与α－双炔失碳酯对钙调蛋白功能的抑制有关。α－双炔失碳酯对钙调蛋白激活的Ｃａ２＋．Ｍｇ２＋－ＡＴＰ酶和钙调蛋白依赖性磷酸二酯酶的活力都有较明显的抑制作用，提示α－双炔失碳酯对钙信号系统的干扰可能与其抗肿瘤作用密切相关。     

钙调蛋白拮抗剂苄基异喹啉类化合物对培养的成纤维细胞的作用机理研究

本文将牛血清白蛋白(BSA)与钙调蛋白(Calmodulin,CaM)交联作为抗原,制备抗体,运用酶联免疫吸附法(ELISA)建立了测定CaM含量的标准曲线,通过EL ISA和流式细胞光度计观察了CaM拮抗剂0—(1—ethoxyl—bUtyl)berbarmine(EBB)对培养的成纤维细胞的CaM和DNA的影响,探讨了EBB的作用机理。     

抗钙调素单克隆抗体的制备及开发利用

目的：抗钙调素单克隆抗体的制备及开发利用。方法：以碳化二亚胺法将钙调素-卵清蛋白偶联物作为免疫原，采用常规免疫方法免疫BALB/c小鼠，杂交瘤技术制备抗牛脑钙调素单克隆抗体。酶联免疫吸附法(ELISA)检验，应用硫酸铵盐析法进行了抗体的纯化。结果：采用免疫印迹、免疫酶斑点法及液相竞争法鉴定了抗钙调素单克隆抗体的性质，表明该抗体对钙调素有较强的特异性。结论：此研究制备出的高特异性、高亲和力及高效价的抗牛脑钙调素单克隆抗体可用于胞外钙调素促进皮肤创伤修复的基础研究，也可用于免疫学定量分析、免疫学定位分析及共沉淀分析，具有较好的经济价值。     

二甲双胍对大鼠垂体-性腺轴钙调蛋白mRNA表达的影响

目的研究二甲双胍(metformin,MF)对大鼠垂体—性腺轴钙调蛋白(calmodulin,CaM)mRNA表达的影响。方法采用实时荧光定量逆转录聚合酶链反应(RT-PCR)技术,系统观察MF对大鼠垂体—性腺轴钙调蛋白mRNA表达的影响。结果MF270mg·kg-1·d-1,ig,连续给药21d,可抑制大鼠睾丸细胞CaM mRNA的表达(P<0.01),而对垂体分泌细胞CaM mRNA的表达则无明显影响。结论二甲双胍可抑制大鼠睾丸细胞CaM mRNA的表达。     

Peptides related to the calcium binding domains II and III of calmodulin

Three hexadecapeptides which correspond to the putative Ca²⁺ binding domains II and III of calmodulin were synthesized employing solid phase methodology. One of the peptides contained an internal cystine bridge which was formed while the corresponding linear peptide was still attached to the polymeric carrier. The interaction of the synthetic peptides with calcium ions was investigated using Tb³⁺mediated fluorescence. Binding was of the order Cal2 > Cal3 > Cal3C (Fig. 1) with binding constants K_Tb= 0.68 times 10^-5, 0.54 times 10^-5, and 0.21 times 10^-5 M^-1 respectively. Biological activity of the compounds was assessed by measuring their stimulatory effect on erythrocyte membrane (Ca²⁺⁺ Mg²⁺)-ATPase activity For 50% activity as compared with CaM, the concentration of peptides required was for Cal2, Cal3 and Cal3C, 50, 100 and 167 times higher than CaM, respectively. The results suggest that the three synthetic peptides possess certain calmodulin-like features.     

Interaction of calmodulin with synthetic deletion peptides of melittin

The 26-residue peptide melittin present in bee venom has been shown to bind calmodulin tightly. In this study we synthesized the following series of deletion peptides of melittin by the solid-phase method: Mel12, Mel13, Mel 14, Mel 15, Mel15F. The results of this study show that the deletion peptides Mel 14 and Mel 15 have almost the same binding activity as the intact native peptide. Each deletion peptide forms a 1:1 complex with calmodulin according to electrophoresis analysis. When the tryptophanyl residue of Mel15 was replaced by the phenylalaninyl residue, the dissociation constant of the peptide—calmodulin complex increased. This shows the importance of the tryptophanyl residue for binding to calmodulin.