1-(4-烃氧基)苄基四氢异喹啉类化合物及相关化合物的合成与生物活性

以有心血管活性的异喹啉生物碱为先导物，设计合成了１５个３，４二氢（ＩＩ１，２）和１，２，３，４四氢（４烃氧基）苄基四氢异喹啉化合物（ＩＩ３～１５）。药理实验表明：大部分化合物有舒张血管条作用，其中化合物ＩＩ９对低钾诱导的血管收缩有较强的抑制作用，而对高钾诱导的血管收缩无作用，对硝酸乌头碱诱发的大鼠室性心律失常有明显保护作用。     

去葡萄糖竹节参皂苷Ⅳa抗实验性心律失常作用

目的研究去葡萄糖竹节参皂苷Ⅳa(DCⅣa)是否具有抗实验性心律失常的作用。方法采用氯化钡、乌头碱、毒毛花苷G及结扎左冠状动脉前降支诱发大鼠或豚鼠心律失常模型,八道生理记录仪观察并记录Ⅱ导联心电图,观察DCⅣa对实验性心律失常的预防作用。结果DCⅣa能缩短氯化钡和乌头碱诱发大鼠心律失常的持续时间,增加恢复正常心律的动物数;增加诱发豚鼠心律失常的毒毛花苷G用量;延长冠脉结扎致大鼠心律失常发生的潜伏期,缩短心律失常的持续时间,降低室颤发生的百分率。结论DCⅣa具有明显的抗心律失常作用。     

4′甲基-7-(2-羟基-3-异丙胺基丙氧基)黄酮盐酸盐的抗实验性心律失常作用

4'-甲基-7-(2-羟基-3-异丙胺基丙氧基)黄酮盐酸盐(SIPI-549)对乌头碱诱发的大鼠心律失常有预防作用,对氯化钡诱发的家兔心律失常有治疗作用,对哇巴因诱发的豚鼠心律失常则无明显作用。抗心律失常作用比普萘洛尔强,但比胺碘酮弱。对狗急性心肌梗塞后24 h 的心律失常,本品的抗心律失常作用比利多卡因弱,但负性频率作用比其为强。     

1-(4-烃氧基)苄基四氢异喹啉类化合物及相关化合物的合成与生物活性

以有心血管活性的异喹啉生物碱为先导物,设计合成了15个3,4-二氢(II_1,2)和1,2,3,4-四氢-(4-烃氧基)苄基四氢异喹啉化合物(II_3～15)。药理实验表明:大部分化合物有舒张血管条作用,其中化合物II₉对低钾诱导的血管收缩有较强的抑制作用,而对高钾诱导的血管收缩无作用,对硝酸乌头碱诱发的大鼠室性心律失常有明显保护作用。     

1-甲基-1,2,3,4-四氢异喹啉的简易合成

目的制备1-甲基-1,2,3,4-四氢异喹啉。方法以苯乙胺为原料,经酰化反应得乙酰苯乙胺,在多聚磷酸的作用下环合得1-甲基-3,4-二氢异喹啉,经硼氢化钠还原得1-甲基-1,2,3,4-四氢异喹啉。结果反应总收率80%,比文献收率提高了10%,产物结构由1H-NMR光谱确证。结论经酰化、环合、还原三步反应制备1-甲基-1,2,3,4-四氢异喹啉的方法简单,原料便宜,处理容易,副产物较少。     

1-［1-(6-甲氧基-2-萘基)乙基］-2-(4-硝基苄基)-6,7-二甲氧基-1,2,3,4-四氢异喹啉氢溴酸盐的光降解产物研究

研究1-［1-(6-甲氧基-2-萘基)乙基］-2-(4-硝基苄基)-6,7-二甲氧基-1,2,3,4-四氢异喹啉氢溴酸盐(编号P91024)遇光后颜色变暗的光降解产物。采用HPLC-MS及波谱分析鉴定光降解产物的化学结构，并经有机反应合成对照验证。P91024光降解的3个主要产物分别为溴化N-(4-硝基苄基)-6,7-二甲氧基-3,4-二氢异喹啉、1-［1-(6-甲氧基-2-萘基)乙基］-6,7-二甲氧基-1,2,3,4-四氢异喹啉和2-异丙基-6-甲氧基萘。     

3,6-(二甲氨基)-二苯并碘杂六环葡萄糖酸盐抗心律失常作用

在氯化钡 (BaCl2 ) ,氯仿 肾上腺素 ,毒毛花苷G ,乌头碱 ,乙酰胆碱 氯化钙 (ACh CaCl2 ) 5种实验性心律失常模型上观察了 3,6 (二甲氨基 ) 二苯并碘杂六环葡萄糖酸盐 (IHC 93)对抗心律失常的作用 .结果表明IHC 930 .2 5和 0 .50mg·kg- 1均可对抗ACh CaCl2 诱发的小鼠房颤 (扑 ) ;明显缩短BaCl2诱发的大鼠室性心律失常持续时间 ;对氯仿 肾上腺素诱发家兔的心律失常有预防及缓解作用 ;能提高毒毛花苷G致豚鼠室性早搏 ,室性心动过速 ,室颤和心搏停止的用量 ;能提高乌头碱导致室性早搏用量 ,对室性心律失常有部分对抗作用 .     

四氢异喹啉类衍生物P91024对实验性心律失常和豚鼠离体心房肌的作用

目的:研究四氢异喹啉类衍生物P91024[化学名:1-{1-(6-甲氧基-2-萘基)乙基}-2-对硝基苄基-6,7-二甲氧基-1,2,3,4-四氢异喹啉氢溴酸盐]对实验性心律失常和豚鼠离体心房肌的作用.方法:采用氯化钙、氯化钡、肾上腺素诱导心律失常动物模型,观察灌胃给P91024对实验性心律失常的作用.采用豚鼠离体心房肌实验方法,测定P91024给药前后对心房静息后增强及正性阶梯现象的影响.结果:P91024 30和60 mg·kg-1能降低氯化钙诱发大鼠室颤的发生率(P＜0.01),缩短窦律恢复时间(P＜0.05).P91024 60mg·kg-1可缩短氯化钡诱发大鼠心律失常的持续时间(P＜0.05).并且,P91024 26.1和52.2 mg·kg-1能缩短肾上腺素诱发豚鼠心律失常的持续时间(P＜0.05).P91024 5×10-5mol·L-1能明显翻转豚鼠离体心房肌的正性阶梯作用(P＜0.01)和降低静息后增强作用(P＜0.01).结论:P91024具有明显的抗实验性心律失常作用,抑制豚鼠离体心房肌静息后增强现象及翻转正性阶梯现象.显示本品可能是一种特异性钙拮抗剂.     

二乙酰关附甲素抗实验性心律失常的作用

采用４种动物实验性心律失常模型，观察了二乙酰关附甲素（关附乙素，ＤＧＦＡ）的抗心律失常作用。结果表明，ＤＧＦＡ能显著对抗乌头碱诱发的大鼠室性早搏、室性心动过速和室性纤颤；明显对抗氯化钙诱发的大鼠室颤和氯仿诱发的小鼠室颤；明显对抗大鼠结扎左冠状动脉所致心律失常，减少室性早搏的发生次数，延迟首次室性早搏的出现时间，降低室生心动过速的发生率。其作用机制可能主要与其阻滞心肌细胞的Ｎａ＋、Ｃａ２＋通道有关。     

毛果芸香碱对实验性心律失常的保护作用

目的：观察毛果芸香碱对实验性心率失常的影响。方法：分别以乌头碱，氯化钡和哇巴因制备实验性动物心律失常模型，观察毛果芸香碱的干预作用。结果：毛果芸香碱可显著延迟乌头碱引起的大鼠室性心律失常的出现（P〈0．05），延长出现心律失常后的存活时间（P〈0．05）；能明显延迟氯化钡引起的大鼠双相室性心律失常的出现（P〈0．01），缩短心律失常的持续时间（P〈0．01）；能显著延长哇巴因引起豚鼠出现心律失常后的存活时间（P〈0．05）。毛果芸香碱的上述作用可被M3受体阻断荆4-DAMP完全逆转。结论：毛果芸香碱具有对抗乌头碱和氯化钡诱发大鼠，哇巴因诱发豚鼠心律失常的作用，提示其具有良好的抗心律失常作用；毛果芸香碱通过激动大鼠和豚鼠心肌M3受体而产生抗心律失常的作用。     

Synthese des 6,7-Dimethoxy-3-(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisochinolins

Synthesis of 6,7-Dimethoxy-3-(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline The synthesis and chemical reactivity of 6,7-dimethoxy-3(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (I) are described.     

卡维地洛抗实验性心律失常作用

目的　评价卡维地洛（ＣＶＤ）抗实验性心律失常作用,并与β受体阻断剂普萘洛尔（ＰＲＯ） 进行比较。方法　采用氯仿致小鼠室颤（ＶＦ） , 哇巴因、乌头碱致豚鼠、大鼠心律失常,肾上腺素致豚鼠心律失常, 以及结扎大鼠冠状动脉诱发心律失常等５ 种模型。结果　与溶媒对照组相比, ＣＶＤ１ ｍｇ·ｋｇ－１ 显著降低氯仿诱发的小鼠ＶＦ 发生率〔１８－７５ ％（３／１６） ｖｓ８１－２５％ （１３／１６）,Ｐ＜ ０－０１〕,此作用与ＰＲＯ 相似。１ ｍｇ·ｋｇ－１ ＣＶＤ 和ＰＲＯ 均显著提高致室早（ＶＥ） , 室速（ＶＴ）, ＶＦ, 心搏停止（ＣＡ） 所需哇巴因和乌头碱用量（ Ｐ＜０－０１ ｖｓ 溶剂对照组） ;ＣＶＤ 对抗哇巴因的致心律失常作用较等剂量ＰＲＯ 显著（ Ｐ＜ ０－０１ ,ＣＶＤ ｖｓ ＰＲＯ）。ＣＶＤ 剂量依赖性地显著缩短ｉｖ 肾上腺素４０ μｇ·ｋｇ－ １ 所致心律失常持续时间,有效减少结扎冠脉诱发的缺血性心律失常ＶＴ,ＶＦ,ＣＡ 的发生率并缩短ＶＴ 的持续时间。结论　ＣＶＤ 具有抗多种实验性心律失常作用,该作用在等剂量时至少与ＰＲＯ 相近,或强于ＰＲＯ。ＣＶＤ的这种作用最终将有益于接受其治疗的原发性高血压、冠心病、充血性心力衰竭患者     

Antiarrhythmic effects of two new propafenone related drugs. A study on four animal models of arrhythmia

LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropylamino)-propoxy)-4-methyl- 2-thienyl]-3-phenyl-1-propanone, hydrochloride) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenone, hydrochloride) are two new antiarrhythmic drugs. They are structurally related to propafenone which is a widely used class 1 antiarrhythmic drug with relatively low bioavailability. Both substances were characterized in four animal models of arrhythmia and compared to propafenone. In isolated guinea pigs left auricles LG 6-101 and LG6-102 were about twice as effective as propafenone regarding the prolongation of the functional refractory period but did not decrease contractility more than propafenone. LG 6-101 was significantly more effective (p less than or equal to 0.002) than propafenone or LG 6-102 in delaying the onset of ventricular premature beats in ouabain induced arrhythmias in guinea pigs. In aconitine induced arrhythmias in rats, LG 6-101 and LG 6-102 did not differ in their antiarrhythmic effects from propafenone, whereas the protection against cardiac arrest was significantly (p less than or equal to 0.003) better for LG 6-101 than for propafenone or LG 6-102. In arrhythmias induced by occlusion of the left descending coronary artery in rats the drugs tested showed as good antiarrhythmic effects as propafenone. In this model the size of the ischemic area was also measured and LG 6-101 was the most effective drug in that respect. These results suggest that both LG 6-101 and LG 6-102 are potent antiarrhythmic substances which in some models were more effective than propafenone.     

青蒿素抗心律失常作用及机制

目的　观察青蒿素抗心律失常作用,并探讨其作用机制。方法　采用冠脉结扎,氯化钙,氯仿所致心律失常模型进行青蒿素的抗心律失常作用研究。应用膜片钳技术研究药物对内向整流钾电流的作用。结果　青蒿素能明显对抗结扎冠脉引起的心律失常,对氯化钙、氯仿引起的心律失常,可使其发生时间明显延长,室颤明显减少。膜片钳实验表１９９８ ０２ ２０ 收稿,１９９９ ０４ １４ 修回作者简介：李宝馨,女,３５ 岁,副教授,博士,主要从事心血管药物研究;杨宝峰,男,４１ 岁,博士后,博士生导师,哈尔滨医科大学副校长,主要从事抗心律失常药物研究明,该药可剂量依赖性的明显抑制内向整流钾电流。结论　该药是一有效的抗心律失常药,其作用机制与其抑制内向整流钾电流有关     

碘化N-正丁基氟哌啶醇对抗氯化钡引起心律失常的作用

目的研究碘化N-正丁基氟哌啶醇对抗BaCl2引起心律失常的作用。方法采用氯化钡诱导的心律失常动物模型,观察碘化N-正丁基氟哌啶醇对抗BaCl2引起心律失常的作用。结果碘化N-正丁基氟哌啶醇(0.5、1、2、4mg/kg)可剂量依赖的减少氯化钡诱发心律失常的发生率,缩短心律失常的持续时间。结论碘化N-正丁基氟哌啶醇具有明显的对抗BaCl2引起心律失常的作用。     

Hyperactivity induced by tetrahydroisoquinoline derivatives injected into the nucleus accumbens.

Several derivatives of tetrahydroisoquinoline were injected bilaterally into the nucleus accumbens of rat 2 h after a nialamide pretreatment and activity recorded in cages fitted with photocells. 1,2,3,4-Tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-6,7-dihydroxy-1-(3,4-dihydroxybenzyl)-isoquinoline (tetrahydropapaveroline) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused virtually no change in locomotor activity and 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused only modest hyperactivity responses. However, 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both shown to markedly increase activity in a dose-dependent manner. Of these two compounds, the 3-methyl-6,7-methylenedioxyderivatives was most active and equalled the effectiveness of dopamine. The responses to dopamine and to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both threshold at 3.125 mug and maximum at 50 mug. Both effects developed within 1-2 h and persisted for at least 6 h. The hyperactivity induced by dopamine was antagonised in a dose-dependent manner by haloperidol: propranolol and aceperone were without effect. Similar results were obtained for these blocking agents against the responses to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline but aceperone and propranolol, in addition to haloperidol, were shown to inhibit the hyperactivity induced by 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.     

Investigation of new benzofurane, benzopiran and furanochromone derivatives--potential antiarrhythmic and hypotensive agents

Eight newly synthesized compounds were tested in respect of their acute toxicity, antiarrhythmic activity, influence on the electrogenic action of the heart and blood pressure. The most active benzofuran derivative was 2-acetyl-3-methyl-6 methoxy-7-(2'hydroxy-3'-isopropylaminopropoxy)benzofuran, the most active benzopiran: 4-methyl-6,7-dimethoxy-8-(2'-isopropylaminopropoxy)benzo-alpha- piron. Of furachromone derivatives the expected properties were displayed only by 2-methyl-5-carbamoylmethoxy-8-diisopropylaminofuro-3,2-g-chr omone.     

Effects of azimilide, a KV(r) and KV(s) blocker, on canine ventricular arrhythmia models.

Using canine coronary artery ligation/reperfusion and adrenaline arrhythmia models, we determined the effects of azimilide, a class III antiarrhythmic agent, E-1-[[(5-(4-chlorophenyl)-2-furanyl) methylene]-amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidi nedione dihydrochloride. The coronary ligation/reperfusion arrhythmia experiments were divided into two groups, one using low heart rate halothane-anesthetized and the other using high heart rate pentobarbital-anesthetized dogs. Azimilide (6 mg kg(-1) + 0.1 mg kg(-1) min(-1) i.v.) prolonged the corrected QT interval (QTc), decreased the heart rate and suppressed the premature ventricular complexes during ligation (35 +/- 17 beats/30 min as compared with 909 +/- 246 in the control group), and also suppressed ventricular fibrillation induced by coronary ligation/reperfusion in the two groups (1/8 halothane-anesthetized dogs as compared with 7/8 dogs in the control group and 2/8 pentobarbital-anesthetized dogs as compared with 8/8 dogs in the control group). In adrenaline arrhythmia, azimilide hastened the onset of adrenaline arrhythmias and also aggravated the arrhythmias, showing proarrhythmic effects.