苄普地尔降低左甲状腺素诱发升高的大鼠脑线粒体钙~（2＋）镁~（2＋）－ATP酶活力

苄普地尔降低左甲状腺素诱发升高的大鼠脑线粒体钙２＋镁２＋ＡＴＰ酶活力陈丁丁，戴德哉，储永新（中国药科大学药理研究室，南京２１０００９，中国）关键词钙通道阻滞剂；苄普地尔；普萘洛尔；左甲状腺素；大脑；线粒体；钙２＋镁２＋ＡＴＰ酶目的：研究苄普地尔是...     

普萘洛尔和苄普地尔消除左甲状腺素诱发的大鼠心脏肥厚和线粒…

目的：研究普萘洛尔和苄普地尔对左甲状腺素诱发的大鼠心脏肥厚及其线粒体Ｃａ＾２＋Ｍｇ＾２＋－ＡＴＰ酶活力升高的影响。 方法：ｉｐ左甲状腺素１ｍｇ·ｋｇ＾－１·ｄ＾－１×１０ｄ，诱发大鼠心脏肥厚，然后ｉｇ普萘洛尔或苄普地尔１０ｍｇ·ｋｇ＾－１·ｄ＾－１×３ｄ治疗Ｃａ＾２＋Ｍｇ＾２＋－ＡＴＰ酶活力及其酶动力学参数测定。 结果：肥厚左室线粒体Ｃａ＾２＋Ｍｇ＾２＋－ＡＴＰ酶活力和Ｖｍａｘ分别为２５±４和３５     

苄普地尔消退L－甲状腺素诱发的大鼠心肌肥厚及其质膜Ca~（2＋），Mg~（2＋

研究了苄普地尔对Ｌ－甲状腺素（１ｍｇ·ｋｇ－１·ｄ－１×７ｄ）诱发的大鼠心肌肥厚和心肌质膜Ｃａ２＋，Ｍｇ２＋－ＡＴＰ酶活力增高的影响，经苄普地尔１０或２０ｍｇ·ｋｇ－１·ｄ－１ｐｏ治疗３ｄ后，心肌肥厚及其升高的Ｃａ２＋，Ｍｇ２＿－ＡＴＰ酶活力和Ｖｍａｘ均降至正常，但甲状腺素引起的该酶对ＡＴＰ的亲和力降低未被苄普地尔改变。苄普地尔组左心室蛋白质含量较未治疗组亦显著减少，但未恢复至正常。结论：苄普地尔消退Ｌ－甲状腺素诱发的大鼠心肌肥厚，心肌Ｃａ２＋，Ｍｇ２＋－ＡＴＰ酶活力增高和蛋白质生物合成的增加。     

乌贼墨对H_(22)癌细胞内Ca~(2 )、ATP浓度及线粒体Ca~(2 )/Mg~(2 )-ATP酶活性的影响

利用荧光探针和荧光素,研究了乌贼墨对Ｈ_(２２)癌细胞内 Ｃａ~（２＋）、ＡＴＰ浓度及线粒体Ｃａ~（２＋）／Ｍｇ~（２＋）－ＡＴＰ酶活性的影响。结果发现,乌贼墨使Ｈ_(２２)癌细胞内Ｃａ~（２＋）浓度降低了２．３和３．７倍,线粒体Ｃａ~（２＋）／Ｍｇ~（２＋）－ＡＴＰ酶活性降低了 ２８％和 ５８％,ＡＴＰ浓度升高 Ｔ ７７％和 ８３％。结果提示乌浓墨可能通过降低细胞内Ｃａ~（２＋）浓度,继而影响到线粒体上Ｃａ~（２＋）依赖性Ｃａ~（２＋）／Ｍｇ~（２＋）-ＡＴＰ酶活性,减少了Ｃａ~（２＋）向线粒体内的转运,减轻甚至消除了Ｃａ~（２＋）对ＡＴＰ合成的抑制作用。这可能是乌贼墨抑制肿瘤生长的机制之一。     

苄普地尔降低左甲状腺素诱发升高的大鼠脑线粒体钙^2＋镁^2＋—A…

研究苄普地尔是否能影响左甲状腺素诱发升高的大鼠脑线粒体钙＾２＋镁＾２＋－ＡＴＰ酶活力及其与缺血性超负荷钙脑损伤的关系。     

牛磺酸对缺血大鼠心肌腺苷三磷酸酶的影响

目的观测牛磺酸（ｔａｕｒｉｎｅ，Ｔａｕ）对心肌缺血损伤时心肌肌膜和线粒体ＡＴＰ酶活性的影响。方法以异丙肾上腺素（Ｉｓｏ，５ｍｇ·ｋｇ－１）诱导心肌缺血损伤模型，用定磷法分别测定Ｃａ２＋－ＡＴＰ酶、Ｍｇ２＋－ＡＴＰ酶及Ｎａ＋，Ｋ＋－ＡＴＰ酶活性。结果与对照组比较，缺血组心肌肌膜和线粒体Ｃａ２＋－ＡＴＰ酶、Ｍｇ２＋－ＡＴＰ酶及Ｎａ＋，Ｋ＋－ＡＴＰ酶活性均降低，在注射ＩＳＰ前３０ｍｉｎ腹腔注射Ｔａｕ（２００ｍｇ·ｋｇ－１），则上述酶活性未见显著性变化。结论Ｔａｕ具有拮抗缺血大鼠心肌肌膜及线粒体Ｃａ２＋－ＡＴＰ酶、Ｍｇ２＋－ＡＴＰ酶及Ｎａ＋，Ｋ＋－ＡＴＰ酶活性降低的细胞保护作用     

乌贼墨对H22癌细胞内Ca^2＋,ATP浓义及线粒体Ca^2＋／Mg^2＋—ATP酶？…

利用荧光探针和荧光素,研究了乌贼黑对Ｈ２２癌细胞内Ｃａ＾２＋、ＡＴＰ浓度及线粒体Ｃａ＾２＋／Ｍｇ＾２＋－ＡＴＰ酶活性的影响。结果发现,乌贼墨使Ｈ２２癌细胞内Ｃａ＾２＋浓度降低了２．３和３．７倍,线粒体Ｃａ＾２＋／Ｍｇ＾２＋－ＡＴＰ酶活性降低了２８％和５８％,ＡＴＰ浓度升高了７７％和８３％．     

维拉帕米对大鼠脑突触体内Ca^2＋和Ca^（2＋）Mg^（2＋）—ATP酶的影响

维拉帕米１０，５０和１００μｍｏｌ．Ｌ＾－１能增加高Ｋ＾＋和去甲肾上腺素所致大鼠脑突触体内激离Ｃａ＾２＋的浓度，但使静息状态突触体内游离Ｃａ＾２＋浓度下降。Ｖｅｒ还抑制突触体Ｃａ＾（２＋）Ｍｇ＾（２＋）－ＡＴＰ酶活性。结果提示：与静息状态不同，在神经末梢受到刺激时，Ｖｅｒ可能是通过抑制ＣａＭ，进而抑制Ｃａ＾（２＋）Ｍｇ＾（２＋）－ＡＴＰ酶活性，使胞浆内游离Ｃａ＾（２＋）升高，引起递质释放量增加。     

氯丙烯对神经细胞胞浆膜和线粒体膜 Ca~(2 )-ATP 酶,Na~ ,K~ -ATP 酶活性的影响

氯丙烯对神经细胞胞浆膜和线粒体膜Ｃａ２＋┐ＡＴＰ酶，Ｎａ＋，Ｋ＋┐ＡＴＰ酶活性的影响张磊谢克勤高树君孙克任（山东医科大学毒理学研究室，济南２５００１２）用鸡胚脑神经细胞研究１－烯丙基氯－３对细胞胞浆膜和线粒体膜Ｃａ２＋－ＡＴＰ酶，Ｎａ＋，Ｋ＋－ＡＴＰ...     

The Effects of Etimicin and Gentamicin on Renal Endoplasmic Reticulum ~(45)Ca~(2 )-Uptake and Ca~(2 )-Mg~(2 )-ATPase Activity

目的：研究爱大霉素和庆大霉素对大鼠肾皮质内质网４５Ｃａ２＋摄取以及对内质网膜上Ｃａ２＋Ｍｇ２＋ＡＴＰａｓｅ活性的影响。方法：４５Ｃａ２＋示踪技术和孔雀蓝分光光度法。结果：爱大霉素和庆大霉素在大于或等于３．４×１０４ｍｏｌ·Ｌ１时，能抑制内质网４５Ｃａ２＋摄取（抑制率分别大于或等于１７．４％和２５．５％）；在３．４×１０２ｍｏｌ·Ｌ１时，对内质网膜上Ｃａ２＋Ｍｇ２＋ＡＴＰａｓｅ活性有抑制作用（抑制率分别为２４．１７％和２９．１９％）。结论：爱大霉素和庆大霉素在较高浓度时可使胞浆钙升高，这可能与其产生肾毒性有关     

2-吡啶甲醇及2-吡啶甲醛的合成

以 2 -甲基吡啶为原料、过氧化氢为氧化剂制备 2 -吡啶甲醇和 2 -吡啶甲醛,工艺方法经济、安全     

Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.     

2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

Metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine

The metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine were studied to elucidate the biochemical basis for their known cytotoxicities. 2-Azaadenosine is a known substrate for adenosine kinase. That 2-azahypoxanthine is a substrate for hypoxanthine (guanine) phosphoribosyltransferase is shown by the observations that, in cell-free fractions from HEp-2 cells supplemented with 5-phosphoribosyl-1-pyrophosphate, 2-azahypoxanthine inhibited the conversion of hypoxanthine to IMP but not the conversion of adenine to AMP, and hypoxanthine, but not adenine, inhibited the conversion of 2-azahypoxanthine to 2-azaIMP. [8-14C]2-Azahypoxanthine was synthesized from [8-14C]hypoxanthine via [2-14C]-4-amino-5-imidazolecarboxamide. In HEp-2 cells in culture, the principal metabolite of [8-14C]-2-azahypoxanthine was 2-azaATP; there was no detectable 14C in deoxynucleotides or in DNA or RNA fractions. 2-Azaadenosine was much more toxic than 2-azahypoxanthine, and, when used in the presence of an adenosine deaminase inhibitor, 2'-deoxycoformycin, was converted in HEp-2 cells to 2-azaATP in amounts that exceeded those of ATP in control cells. The pool of ATP was reduced by as much as 75% as 2-azaATP accumulated. In a short-term experiment (4 hr), 2-azaadenosine selectively reduced the pools of adenine nucleotides, whereas 2-azahypoxanthine reduced the pools of guanine nucleotides selectively. Both 2-azahypoxanthine and 2-azaadenosine inhibited the incorporation of formate into purine nucleotides and were without effect on the conversion of thymidine and uridine to nucleotides. 2-Azahypoxanthine inhibited the incorporation of thymidine into macro-molecules but not that of uridine or leucine; 2-azaadenosine inhibited the incorporation of all three of these precursors non-selectively. 2-AzaIMP inhibited IMP dehydrogenase competitively with IMP (Ki = 66 microM). The difference in effects of 2-azahypoxanthine and 2-azaadenosine perhaps may be due to the production, from 2-azahypoxanthine but not from 2-azaadenosine + 2'-deoxycoformycin, of 2-azaIMP, which inhibits synthesis of guanine nucleotides and thereby results in inhibition of DNA synthesis. Specific sites of action for 2-azaadenosine are yet undefined.     

Molecular modeling of 2-alkyloxy- and 2-aralkyloxy-adenosine A1- and A2-agonists

The C2-region of adenosine A1- and A2-receptors by a molecular modeling technique has been extended and applied to a series of 2-substituted adenosines reported by Olsson, et al. The similarity and dissimilarity of the structure maps obtained by molecular modeling have been used as a basis for the mapping of the analysed receptor domain. The proposed model of the C2-region of the A1-receptor consists of a narrow and sterically limited area that interacts well electrostatically with small and electron rich moieties. Olsson's provisional model of the C2-region of the A2-receptor has been extended with two subsites, as well as with a forbidden area near the C2-position of the purine ring. The conformational analysis performed in the study does not support the hypothesis of Olsson et al. that adenosine C2 substituents may partly occupy the same receptor domain as the N6 substituents of the A1-receptor. The occupation of the cycloalkyl subsite increases the receptor selectivity while the occupation of the other subsite by aryl rings, fixed at a parallel position to the purine system, highly enhances the receptor affinity.     

Synthesis and antiviral evaluation of carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine

Carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine, compounds 8 and 9, were synthesized by an eight-step synthesis from (+/-)-(1 alpha,2 alpha,3 beta,5 beta)-3-amino-5-(hydroxymethyl)-1,2- cyclopentanediol (1), which was prepared from cyclopentadiene via an eight-step route. These compounds were tested in vitro against herpes simplex virus type 1 (HSV-1). The 2'-amino analogue was found to show moderate antiviral activity, with an ED50 of 50 microM. However, the 2'-azido analogue was not active at a concentration up to 400 microM.     

2-Fluoroformycin and 2-aminoformycin. Synthesis and biological activity

Syntheses of 2-fluoroformycin [7-amino-5-fluoro-3-(beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine] (2b) and 2-aminoformycin [5,7-diamino-3-(beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine] (2c) are described. Cytotoxicity data are given for 2b and 2c alone as well as with added pentostatin. Kinetic parameters for adenosine deaminase are also provided. 2-Fluoroformycin, although a much poorer substrate for adenosine deaminase than formycin A, is not nearly as cytotoxic to cells in culture.