原小檗碱类生物碱的药理活性

原小檗碱类和四氢原小檗碱类为苄基异喹啉类生物碱的重要组成部分。它们可以由许多科植物中分得。番荔枝科(Annonaceae)、小檗科(Berberidaceae)、旋花科(Convolvulaceae)、蓝堇科(Fumariaceae)、樟科(Lauraceae)、防己科(Menispermaceae)、罂粟科(Papaveraceae)、毛茛科(Ranuculaceae)和芸香科(Rutaceae)为这类生物碱的主要来源。近十年来大量具有原小檗碱结构的化合物被分离出来,其中有些进行了药理研究。它们的主要活性为:抗微生物、降压、镇静、抗白血病和抗肿瘤。     

盐酸巴马汀抗实验性心律失常作用

<正> 巴马汀(Palmatine)属四氢异喹啉类原小檗碱型化合物。以往的研究表明巴马汀有抗肾上腺素、去甲肾上腺素和5一羟色胺的作用.井能竞争性地阻断α和α_2肾上腺素受体、本文研究了盐酸巴马汀对实验性心律失常的药理作用。盐酸巴马汀(palmatine HCI.Pal)由武汉市中联制药厂卜丰思供给,南京药科大学黄枕亚提纯。淡黄色粉末,溶成1%水溶液(pH=6).微温即溶。氯仿—肾上腺素诱发肠鼠心律失常鼠.体重263±34M,兼用,戊巴比妥钠(50mg·kg     

四氢原小檗碱同类物对α1肾上腺素受体的拮抗作用

用放射配体结合实验与离体血管收缩功能实验相结合的方法,研究了4种四氢原小檗碱(tetrahydroproberberine,THPB)同类物对α₁-肾上腺素受体(α₁-AR)的作用。结果显示左旋四氢巴马汀(l-THP),左旋千金藤立陡碱(l-SPD),四氢原小檗碱-18(THPB-18)和四氢小檗碱(THB)¹²⁵IBE2254¹²⁵I-2-β(4-hydroxyphenyl)-ethyaminomethyl-tetralone,¹²⁵IBE)与大鼠脑皮质α₁-AR的结合呈竞争性拮抗作用,pK_I值分别为5.54±0.36,5.56±0.47,5.75±0.56和6.01±0.60,Hill系数接近于1.0。并拮抗苯肾上腺素(phenylephrine,PE)介导大鼠主动脉的收缩,pA₂值分别为5.48±0.58,5.66±0.54,5.64±0.34和5.45±0.76,斜率与1.0无显著性差别。结果提示,4种四氢原小檗碱同类物对α₁-AR均有非亚型选择性拮抗效应,且亲和性相同。     

甘肃小檗枝、叶化学成分的分离与鉴定

目的:对甘肃小檗枝、叶中的化学成分进行分离与鉴定。方法:采用大孔吸附树脂、硅胶、SephadexLH-20等色谱分离手段对甘肃小檗的枝、叶95%乙醇提取物进行分离纯化,根据理化性质和光谱数据鉴定化合物的结构。结果:从甘肃小檗的枝、叶中共分离得到8个化合物,分别鉴定为小檗胺(1)、小檗碱(2)、巴马汀(3)、药根碱(4)、非洲防己胺(5)、小檗红碱(6)、8-氧小檗碱(7)、(+)木兰花碱(8)。其中,化合物5至8为首次从该植物中分离得到。结论:本试验结果可为甘肃小檗的进一步研究提供依据。     

小檗碱的心血管药理作用

小檗碱(Berberine)系异喹啉生物碱,其制剂有多种药理学效应。本文主要报道小檗碱的心血管药理作用及其机理。一、小檗碱对心肌收缩功能及血流动力学的作用据Maroko报道:原小檗碱及其盐有增强哺乳类动物心脏收缩性的效应,显示出较强的正性肌力作用(LVdP/dt和dF/dt的增     

异喹啉类心血管药物研究进展

本文报道了以中草药有效成分为先导物，设计合成了111个异喹啉衍生物包括双苄基异喹啉、苄基异喹啉、原小檗碱等类型化合物，对所合成衍生物进行α-受体，腺苷A1，A2，DHP钙通道放射受体分析以及其它的心血管活性研究，发现化合物VI19具有α1－受体拮抗作用新的钾通道阻滞剂，V9和V21可降低多种动物模型的血压，而无反射性加速心律的副作用，VI13具有抗心律失常和抗室颤作用，该化合物有可能进入临床试验。本文总结了部分化合物的构效关系为进一步研究新化合物提供理论基础。     

小檗碱对兔颈动脉损伤后白介素-6等的影响

目的观察兔颈动脉损伤后炎性因子IL-6、TNF-α、ICAM-1及CRP的动态变化以及小檗碱对其的影响,探讨小檗碱在兔颈动脉血管损伤后对IL-6等炎性因子的作用及其机制。方法30只日本大耳白兔随机分成假手术组(n=6)、模型组(n=6)、小檗碱组(n=9)、辛伐他汀组(n=9),制备兔颈动脉球囊扩张模型。假手术组不用药物,模型组给予生理盐水腹腔注射,小檗碱组2.5?/(kg.d)每日腹腔注射,辛伐他汀组3.3mg/(kg.d)灌胃。于术后第3、6、10d自耳缘静脉取血4m l/只,分离血清,用放射免疫法测定IL-6,TNF-α,用酶联免疫吸附法(ELISA)测定ICAM-1及CRP。结果术后10d,模型组IL-6的浓度明显高于假手术组(P<0.01),也高于辛伐他汀组及小檗碱组(P<0.01);术后3d,模型组TNF-α浓度高于假手术组(P<0.05)及小檗碱组(P<0.01);术后6d模型组TNF-α浓度高于假手术组(P<0.05);术后10d模型组TNF-α高于假手术组(P<0.01)及小檗碱组和辛伐他汀组(P<0.05)。术后6d模型组ICAM-1浓度高于假手术组(P<0.05)、小檗碱组(P<0.01)及辛伐他汀(P<0.05);术后10d模型组ICAM-1高于小檗碱组(P<0.05)。术后3~10d模型组CRP的浓度高于假手术组及小檗碱组(P<0.01,P<0.05)。结论小檗碱对兔颈动脉损伤后IL-6等炎症因子有影响,对动脉损伤后炎症反应有作用。     

几种苯喹嗪类化合物的心血管作用及与α受体的关系

<正> 原小檗碱类生物碱主要分两大类,一为小檗碱类,另为巴马汀类,它们的基本化学结构中都具有苯喹嗪骨架,即具有两个苯环与喹嗪(Quinolize)或多氢喹嗪(Quinolizidine)并合的基本结构。这四个环系的基本结构也可视为并合的双异喹啉核,CA(化学文摘)化学物质索引1983年起将此类化合物列入苯喹嗪项下,可见其主要理化特性与喹嗪关系更为密切。     

小檗碱对葡萄糖吸收的抑制作用

目的研究小檗碱的吸收特性和对肠道葡萄糖吸收的影响,探索小檗碱抗糖尿病作用机制。方法采用在体肠灌流模型观察小檗碱的吸收特性;用Caco-2细胞模型研究小檗碱对肠上皮细胞二糖酶(麦芽糖酶)活力的影响和对葡萄糖转运蛋白的作用。结果小檗碱在肠道内几乎不吸收(2.5 h吸收量小于5%),但能有效抑制小肠上皮细胞上二糖酶活力,其抑制蔗糖酶的ID50为1.830 mg·L^-1;对麦芽糖酶也有抑制作用,但无明显的剂量关系。小檗碱对于葡萄糖在Caco-2细胞上的摄取也有一定抑制作用。结论小檗碱抗糖尿病作用可能主要通过抑制蔗糖酶、麦芽糖酶等二糖酶活力,作为一种α-葡糖苷酶抑制剂发挥其抗糖尿病作用。     

天然产物增强阿霉素抗乳腺癌作用的体外筛选

目的从植物天然产物中筛选具有增强阿霉素抗乳腺癌细胞增殖作用的活性化合物,并对两药联合后的体外抗肿瘤活性进行初步评价。方法采用MTT法研究15种单体化合物对人乳腺癌细胞MDA-MB-231的影响。结果小檗碱、松萝酸、鱼腥草素钠、槲皮素在50μg·mL-1时对MDA-MB-231细胞的抑制率分别为72%(P<0.001),74%(P<0.001),91%(P<0.001)和59%(P<0.01),且具有剂量依赖性。联合用药结果显示,小檗碱与阿霉素联用,CI值小于1。结论小檗碱、松萝酸、鱼腥草素钠、槲皮素对MDA-MB-231细胞的增殖活性具有抑制作用,同时,小檗碱与阿霉素联用具有协同抗肿瘤作用。     

苄基四氢巴马汀对α受体的作用

本实验表明苄基四氢巴马汀(BTHP)具有阻断α-肾上腺素受体的作用。它能竞争性拮抗苯肾上腺素所致大鼠肛尾肌和兔主动脉条的收缩反应,其pA_2值分别为5.86和5.8;也能浓度依赖性地使可乐定和B-HT920的量效曲线平行右移,最大反应不变,其pA_2值分别为5.2和5.3。放射配基结合测定表明,BTHP对α_1和α_2受体均有亲和力,其竞争抑制常数(K_i)分别为3.52μmol/L和8.1μmol/L。     

The effectiveness of alpha 2-adrenoceptor activation increases from the distal to the proximal part of the veins of canine limbs.

1. The effectiveness of alpha 1- and alpha 2-adrenoceptor activation was compared at different levels of the saphenous and cephalic vein of the dog in vitro. 2. Helically cut strips were used to determine concentration-response curves to phenylephrine, noradrenaline, UK-14,304 (5-bromo-6-(imidazoline-2-ylamino)-quinoxaline) and B-HT 920 (2-amino-6-allyl-5,6,7,8-tetra-hydro-4H-(thiazo)-4,5-d-azepine). The effect of prazosin and yohimbine on these curves was also studied. 3. At the distal level, the maximum response to UK-14,304 amounted to 33 and 50% of those to noradrenaline in the saphenous and cephalic vein, respectively, while at the proximal level the maximum response to UK-14,304 amounted to 72 and 78% of those to noradrenaline, in the saphenous and cephalic vein, respectively. 4. In both vessels, the results obtained with B-HT 920 were very similar to those for UK-14,304. 5. The pD2 values for UK-14,304 - which were identical at the three levels of both vessels - and the pA2 values for the antagonism exerted by either prazosin or yohimbine against the responses to UK-14,304 indicate that the alpha 2-adrenoceptors are identical at the different levels of both vessels. 6. These results show that the effectiveness of alpha 2-adrenoceptor stimulation increases from the distal to the proximal regions of canine limb veins. Apparently, this is due to a greater density of alpha 2-adrenoceptors in the proximal regions. 7. Yohimbine is much more potent against phenylephrine distally than proximally in both vessels.(ABSTRACT TRUNCATED AT 250 WORDS)     

The interaction of parafluorohexahydrosiladiphenidol at muscarinic receptors in vitro

1. The antagonistic actions of parafluorohexahydrosiladiphenidol (pFHHSiD) at muscarinic receptors has been studied in cardiac muscle, smooth muscle and cell culture preparations. In this paper, the classification scheme of Doods et al. (1987) is employed. This scheme is based upon differential affinities of muscarinic antagonists. pFHHSiD exhibited high pA2 values at M3 receptors mediating contractions of guinea-pig ileum and oesophageal muscularis mucosae (7.8 and 8.2 respectively) whereas low values were determined at M2 receptors mediating negative inotropic responses in guinea-pig atria (6.0). Intermediate pA2 values were determined at M1 receptors mediating contractions of the canine femoral and saphenous veins. 2. The pA2 values of pFHHSiD at receptors mediating endothelial-dependent relaxation of rat aortic rings, rabbit jugular vein and canine femoral artery (7.6-7.9) were similar to those determined on the ileum. However, the pA2 values of pFHHSiD at receptors mediating contractions of the guinea-pig trachea (7.1), which has been previously shown to possess M3 receptors, were different from those determined in the ileum. 3. The similarity in pA2 values of pFHHSiD between the M3 receptors in guinea-pig ileum and the receptors mediating endothelial-dependent relaxations provide further evidence for the role of M3 receptors in this vascular response. Taken together, pA2 values for pFHHSiD range from 7.1 to 8.2, depending upon the M3 preparation used. The selectivity of the compound therefore for the M3 versus the M2 muscarinic receptor ranged from 13 to 163 fold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological activity of ACC-7513, a selective alpha-adrenoceptor and 5-hydroxytryptamine receptor blocking agent.

The pharmacological activity of N-[2-(2,6-dimethoxyphenoxy) ethyl]-2-(2-methoxyphenoxy) ethanaminium chloride (ACC-7513) was determined in isolated smooth and cardiac muscle and its effect on blood pressure and heart rate assessed in the spontaneously hypertensive rat (SHR). ACC-7513 was found to be a potent alpha-adrenoceptor blocking agent (pA2:8.33) and a 5-hydroxytryptamine (5-HT) antagonist (pA2:7.01), both in rabbit aortic strips. The affinity for alpha-adrenoceptors was about 20 times greater than that for 5-HT-receptors. High concentrations of ACC-7513 did not block histamine in rabbit aortic strips, or beta 1- or beta 2-adrenoceptor responses induced by isoprenaline in guinea-pig right atria and trachea, respectively, but did block cholinoceptor responses induced by carbachol in rat uterus, non-competitively. High concentrations of ACC-7513 also produced sino-atrial depression in guinea-pig right atria and direct relaxation of depolarized rabbit aortic strips. ACC-7513 depressed blood pressure of conscious SHRs and produced a reflex increase in heart rate. The reductions in pressure were modest and of short duration. It is concluded that: (a) ACC-7513 is a potent, selective alpha-adrenoceptor and 5-HT receptor antagonist; and (b) ACC-7513 is not likely to be useful in the treatment of hypertension.     

Characterisation of the contractile activity of eletriptan at the canine vascular 5-HT1B receptor

The functional activity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]- 1 H-indole) at the contractile serotonin (5-hydroxytryptamine; 5-HT) '1B-like' receptor in dog isolated saphenous vein and basilar artery was investigated. Eletriptan, like 5-HT and sumatriptan potently contracted saphenous vein (pEC50: 6.3, 6.9 and 6.1, respectively) and basilar artery (pEC50 7.2, 7.5 and 6.8, respectively). The maximum responses evoked by eletriptan was, unlike sumatriptan, significantly lower than that to 5-HT (intrinsic activity saphenous vein: eletriptan 0.57, 5-HT 1.0, sumatriptan 0.85; basilar artery: eletriptan 0.77, 5-HT 0.98, sumatriptan 0.89). Contractions evoked by eletriptan were antagonised by the 5-HT1B/1D receptor antagonist GR125743 (N-[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide) with pA2 values of 9.1 in saphenous vein and 9.4 in basilar artery. Affinity estimates (pKA) for 5-HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6.6 and 6.3, respectively, compared to the apparent equilibrium dissociation constant (pKp) for eletriptan of 6.8. The rank order of relative intrinsic efficacies (epsilon) was 5-HT > sumatriptan > eletriptan. Thus, eletriptan required greater receptor occupancy (4.4-fold) to evoke an equivalent contraction to 5-HT and sumatriptan in dog isolated saphenous vein. These data demonstrate that eletriptan is a potent partial agonist at the canine vascular 5-HT1B receptor.     

Cardiovascular properties of medroxalol, a new antihypertensive drug

Medroxalol is a new antihypertensive agent that is presently undergoing clinical trial. Its cardiovascular properties were studied using spontaneously hypertensive rats (SHR), anesthetized dogs, and isolated tissues. Medroxalol produced a long-lasting fall in blood pressure when given by the oral route to SHR. It was more potent than phentolamine in antihypertensive effectiveness. Given intravenously to dogs, medroxalol reduced the blood pressure and heart rate of doses that did not greatly reduce cardiac output. The hypotensive effect of medroxalol was reduced but not abolished following alpha- and beta-adrenergic-receptor blockade. Medroxalol inhibited heart rate and blood pressure responses to isoproterenol and phenylephrine in dogs. In vitro medroxalol resembled a competitive antagonist at alpha-adrenergic receptors in rabbit aortic strips (pA2 6.09) and beta-adrenergic receptors in guinea pig atria (pA2 7.73). It was 0.02 as potent as phentolamine at alpha-receptors and 0.09 as potent as propranolol at beta-receptors. It was concluded that the principal action of medroxalol was to produce a fall in blood pressure by decreasing peripheral vascular resistance more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does not satisfactorily explain the hypotension. A contribution by an active vasodilatory component appears likely.     

Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs

We examined the effect of JTH-601 (3-?N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl?-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system.     

Pharmacological characterization of postsynaptic alpha-adrenoceptor subtypes in five different dog arteries in-vitro

The responses of helically cut strips of arteries isolated from five different sites in the body of dogs to relatively selective alpha 1- and alpha 2-adrenoceptor agonists and the antagonism exerted on these responses by relatively selective alpha 1- and alpha 2-adrenoceptor blockers have been studied. On all arteries (renal, splenic, cranial mesenteric, jejunal and femoral) phenylephrine was a full agonist whereas UK-14,304 was a partial agonist causing maximal contractions of 49, 30, 27, 27 and 10% of the maximum, respectively. Phenylephrine was more potent than UK-14,304, being 9 times more potent in the renal artery and up to 42 times more potent in the cranial mesenteric artery. In the dog saphenous vein, where there are both alpha 1- and alpha 2-adrenoceptors, it has been previously shown that UK-14,304 is 530 times more potent than phenylephrine. Prazosin in low concentrations displaced concentration-response curves for both phenylephrine and UK-14,304 (pA2 values of 8.16-8.43 and 8.13-8.79, respectively) whereas yohimbine was much less potent (pA2 values of 6.53-6.88 and 6.50-7.20, respectively). The results suggest that the alpha-adrenoceptors of all arteries studied are predominantly, if not exclusively, of the alpha 1-subtype.     

Assessment of adrenergic beta-blockade in the anesthetized rat at different baseline values

The influence of different baseline values (blood pressure, heart rate) on ED50- and Emax-values of isoprenaline dose-response curves (DRC) in the presence and absence of beta-blocking drugs was assessed in urethane-anesthetized rats. The results show that Urethane is a suitable anesthetic in this animal model. Different baselines have no influence in ED50-values. Assessment of potency of competitive antagonists (pA2) from complete DRC appears unaffected by differences in baseline or in Emax. Pharmacologic effects (heart rate, blood pressure) are better depicted as absolute effect values than delta-values.