CN106699843B - RGDVGRPAK-The十肽,其制备,活性及应用 - Google Patents
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Abstract
本发明公开了化合物Arg‑Gly‑Asp‑Val‑Gly‑Arg‑Pro‑Ala‑Lys‑The,公开了它的制备方法,公开了它治疗缺血性中风的活性,抗血栓活性和溶血栓活性。因而本发明公开了它在制备治疗缺血性中风,抗血栓和溶血栓药物中的应用。
Description
技术领域
本发明涉及Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The十肽,涉及它的制备方法,涉及它治疗缺血性中风的活性,抗血栓活性和溶血栓活性。因而本发明涉及它在制备治疗缺血性中风,抗血栓和溶血栓药物中的应用。本发明生物医药领域。
背景技术
冠心病、脑卒中以及脉管炎等是非常常见的心脑血管疾病。随着人们生活水平的不断提高,心脑血管疾病的发病人数逐年递增。心脑血管疾病危险因素流行,我国心脑血管疾病的患病率持续上升。据资料统计,每5个成年人中就有1个心血管病患者。血栓形成是心脑血管疾病的重要病因。缺血性脑卒中,具有很高的致死率和致残率。溶栓治疗是常见的重要的手段之一。现有溶栓药物存在出血、再栓塞、再灌注损伤等问题,因此寻找新型的抗缺血性脑卒中新药具有重要的应用价值。在3年的实验研究中,发明人发现Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The十肽具有这样的活性。根据这个发现,发明人提出了本发明。
发明内容
本发明的第一个内容是提供Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The十肽。
本发明的第二个内容是提供Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The的制备方法,该方法包括以下步骤:
(1)Boc-Asp(OMe)与Val-OBzl偶联得到Boc-Asp(OMe)-Val-OBzl;
(2)Boc-Asp(OMe)-Val-OBzl在4N氯化氢的乙酸乙酯溶液中得到L-Asp(OMe)-Val-OBzl;
(3)Boc-Gly与L-Asp(OMe)-Val-OBzl偶联得到Boc-Gly-Asp(OMe)-Val-OBzl;
(4)Boc-Gly-Asp(OMe)-Val-OBzl在4N氯化氢的乙酸乙酯溶液中得到L-Gly-Asp(OMe)-Val-OBzl;
(5)Boc-Arg(Tosh)与L-Gly-Asp(OMe)-Val-OBzl偶联得到Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl;
(6)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl在Pd/C和H2的作用下得到Boc-The-Arg(Tosh)-Gly-Asp(OMe)-Val;
(7)Boc-Ala与Lys(Z)-OBzl偶联得到Boc-Ala-Lys(Z)-OBzl;
(8)Boc-Ala-Lys(Z)-OBzl在4N氯化氢的乙酸乙酯溶液中得到L-Ala-Lys(Z)-OBzl;
(9)Boc-Pro与L-Ala-Lys(Z)-OBzl偶联得到Boc-Pro-Ala-Lys(Z)-OBzl;
(10)Boc-Pro-Ala-Lys(Z)-OBzl在4N氯化氢的乙酸乙酯溶液中得到L-Pro-Ala-Lys(Z)-OBzl;
(11)Boc-Arg(NO2)与L-Pro-Ala-Lys(Z)-OBzl偶联得到L-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(12)Boc-Gly与L-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl偶联得到Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(13)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl在2N NaOH溶液的作用下得到Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z);
(14)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)与The-OBzl偶联得到Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl;
(15)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl在4N氯化氢的乙酸乙酯溶液中得到L-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl;
(16)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val与L-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl偶联得到Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl;
(17)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl
在2N NaOH的甲醇溶液中得到Boc-Arg(Tosh)-Gly-Asp-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The;
(18)Boc-Arg(Tosh)-Gly-Asp-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The在三氟乙酸/三氟甲磺酸(4∶1)溶液中得到Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The.
其中以上所使用的液相方法是本领域的常规并公开的技术。Pd/C是钯/碳,TFA是三氟乙酸,TFMSA是三氟甲磺酸,HCl/EtOAc是氯化氢的乙酸乙酯溶液。
本发明的第三个内容是评价Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The治疗缺血性中风的活性。
本发明的第四个内容是评价Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The的抗血栓活性。
本发明的第五个内容是评价Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The的溶血栓活性。
附图说明
图1 Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The的合成路线.i)HOBt,DCC,NMM,THF;ii)4N HCl/EtOAc;iii)Pd/C,H2;iv)2N NaOH,甲醇;v)TFA,TFMS。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1 制备Boc-Ala-Lys(Z)-OBzl(1)
将2.08g(11mmol)Boc-Ala溶于20mL无水四氢呋喃(THF),冰浴下加入1.35g(10mmol)1-羟基苯并三唑(HOBt)和用无水THF溶解的2.47g(12mmol)二环己基羰二亚胺(DCC),搅拌0.5小时,得反应液A。30分钟后,将4.07g(10mmol)HCl·Lys(Z)-OBzl用15mLTHF溶解,并用N-甲基吗啉先调节pH至9,加入到反应液A中,室温下搅拌12小时,TLC(展开剂CHCl3∶MeOH=30∶1)显示HCl·Lys(Z)-OBzl消失。过滤除去反应液中的二环己基脲(DCU),反应液减压浓缩至干,残留物用100mL乙酸乙酯溶解,滤除不溶物。滤液依次用饱和碳酸氢钠水溶液洗3次,5%硫酸氢钾水溶液洗3次,饱和氯化钠水溶液洗3次,分出的乙酸乙酯层用无水硫酸钠干燥12h,过滤,滤液减压浓缩得到的淡黄色色固体通过硅胶柱柱层析(CH2Cl2∶CH3OH=90∶1)纯化,得到4.0g(74%)标题化合物,为无色固体。ESI-MS(m/z):542[M+H]+。
实施例2 制备HCl·Ala-Lys(Z)-OBzl(2)
将2.0g(3.7mmol)Boc-Ala-Lys(Z)-OBzl溶于少量干燥乙酸乙酯中,冰盐浴下加入20mL 4N氯化氢-乙酸乙酯溶液,冰浴下反应4小时,TLC(CHCl3∶MeOH,30∶1)显示原料点消失,反应完全。反应液减压浓缩,残留物用乙酸乙酯溶解并减压浓缩。该操作重复3次,除净游离的氯化氢,残留物再用无水乙醚磨洗3次,得到1.6g(90%)标题化合物,为无色粉末。ESI-MS(m/z):442[M+H]+。
实施例3 制备Boc-Pro-Ala-Lys(Z)-OBzl(3)
采用实施例1的方法从731mg(3.4mmol)Boc-Pro和1.8g(3.3mmol)HCl·Ala-Lys(Z)-OBzl得到1.7g(78%)标题化合物,为微黄色油状物。ESI-MS(m/z):639[M+H]+。
实施例4 制备HCl·Pro-Ala-Lys(Z)-OBzl(4)
采用实施例2的方法从1.7g(2.5mmol)Boc-Pro-Ala-Lys(Z)-OBzl得到1.4g(92%)标题化合物,为微黄色油状物。ESI-MS(m/z):539[M+H]+。
实施例5 制备Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl(5)
采用实施例1的方法从798mg(2.5mmol)Boc-Arg(NO2)和1.6g(2.4mmol)HCl·Pro-Ala-Lys(Z)-OBzl得到1.5g(71%)标题化合物,为白色固体。ESI-MS(m/z):840[M+H]+。
实施例6 制备HCl·Arg(NO2)-Pro-Ala-Lys(Z)-OBzl(6)
采用实施例2的方法从1.5g(1.8mmol)Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl得到1.2g(86%)标题化合物,为白色粉末。ESI-MS(m/z):740[M+H]+
实施例7 制备Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl(7)
采用实施例1的方法从403mg(2.3mmol)Boc-Gly和1.4g(2.2mmol)HCl·Arg(NO2)-Pro-Ala-Lys(Z)-OBzl得到1.4g(68%)标题化合物,为白色固体。ESI-MS(m/z):897[M+H]+。
实施例8 制备Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)(8)
将1.4g(1.5mmol)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl溶于5mL甲醇中,冰浴下加入2N NaOH水溶液使PH保持在12,反应6小时,TLC显示原料点消失。用饱和硫酸氢钾调pH为7,减压除去甲醇,用饱和硫酸氢钾调PH为2,用乙酸乙酯(30mL×3)反复萃取溶液3遍,合并乙酸乙酯层,用无水硫酸钠干燥,过滤,滤液减压浓缩至干,得1.0g(79%)标题化合物,为白色固体。ESI-MS(m/z):805[M-H]+。
实施例9 制备Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl(9)
采用实施例1的方法从3.0g(3.7mmol)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)和1.1g(3.5mmol)HCl·The-OBzl得到2.8g(72.70%)标题化合物,为白色固体。ESI-MS(m/z):1052[M+H]+。
实施例10 制备HCl·Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl(10)
采用实施例2的方法从1.0g(0.95mmol)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl得到900mg(96%)标题化合物,为白色固体。ESI-MS(m/z):952[M+H]+。
实施例11 制备Boc-Asp(OMe)-Val-OBzl(11)
采用实施例1的方法从2.7g(11mmol)Boc-Asp(OMe)和3.79g(10mmol)Tosh·Val-OBzl得到4.0g(92%)标题化合物,为白色固体。ESI-MS(m/z):437[M+H]+。
实施例12 制备HCl·Asp(OMe)-Val-OBzl(12)
采用实施例2的方法从4.0g(9.2mmol)Boc-Asp(OMe)-Val-OBzl得到3.0g(88%)标题化合物,为微黄色油状物。ESI-MS(m/z):337[M+H]+。
实施例13 制备Boc-Gly-Asp(OMe)-Val-OBzl(13)
采用实施例1的方法从1.42g(8.1mmol)Boc-Gly和3.0g(8.0mmol)HCl·Asp(OBzl)-Val-OBzl得到2.9g(73%)标题化合物,为白色固体。ESI-MS(m/z):494[M+H]+。
实施例14 制备HCl·Gly-Asp(OMe)-Val-OBzl(14)
采用实施例2的方法从2.9g(5.8mmol)Boc-Gly-Asp(OMe)-Val-OBzl得到2.4g(95%)标题化合物,为白色固体。ESI-MS(m/z):394[M+H]+。
实施例15 制备Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl(15)
采用实施例1的方法从2.8g(6.4mmol)Boc-Arg(Tosh)和2.7g(6.3mmol)HCl·Gly-Asp(OBzl)-Val-OBzl得到3.5g(70%)标题化合物,为白色固体。ESI-MS(m/z):803[M+H]+。
实施例16 制备Boc-Arg(Tosh)-Gly-Asp(OMe)-Val(16)
将2.0g(2.5mmol)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl溶于10mL甲醇中,再加入100mg Pd/C(5%),减压排出反应瓶中的空气,通入氢气置换,反复置换5次后,通氢气室温搅拌12小时,TLC(展开剂二氯甲烷∶甲醇=20∶1)显示原料点消失,反应完全,停止反应。滤除Pd/C,滤液减压浓缩除去溶剂,乙醚磨洗,得到1.6g(90%)标题化合物,为白色固体。ESI-MS(m/z):711[M-H]-。
实施例17制备
Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl(17)
采用实施例1的方法从720mg(1.0mmol)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val和900mg(0.91mmol)HCl·Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl得到800mg(53%)标题化合物,为白色固体。ESI-MS(m/z):1647[M+H]+。
实施例18 制备Boc-Arg(Tosh)-Gly-Asp-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The(18)
200mg(0.12mmol)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl溶于20mL甲醇中,冰浴下加入2N NaOH水溶液使pH保持在12,反应6小时,TLC(展开剂二氯甲烷∶甲醇=10∶1)显示原料点消失。用饱和硫酸氢钾调pH至7,减压除去甲醇,得到180mg(97%)标题化合物,为白色固体,ESI-MS(m/z):1543[M+H]+。
实施例19 Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The的合成(19)
将180mg上一步产品Boc-Arg(Tosh)-Gly-Asp-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The加入茄瓶中,冰盐浴下加入1mL TFA和0.25mL TFMSA,1小时后TLC(正丁醇∶水∶冰醋酸=1∶1∶1)显示原料点消失,停止反应,用无水乙醚反复洗涤,减压抽干,然后用水溶解,用25%氨水调pH值至7,用Sephadex G10除盐,C18柱纯化,冻干,得到30mg(22%)标题化合物,为白色粉末。Mp:195-199℃;[α]20 D=-109.09(c=0.11,H2O).IR(KBr):vR-CH3=2962,2873,1450,1381;vR-CH2-R=2930,1257;vCO-NH=1680,3387;vNH2=3400,600.ESI-MS(m/e):1111[M+H]+1H NMR(800MHz,D2O)δ/ppm=0.8917(d,J=6.32Hz,3H),0.8833(d,J=6.32Hz,3H),1.0249(t,J=7.28Hz,3H),1.3328(d,J=7.20Hz,3H),1.3917(m,2H),1.6042(m,2H),1.6316(m,2H),1.6397(m,2H),1.6884(m,2H),1.7724(m,2H),1.8738(m,2H),1.9007(m,2H),1.9518(m,2H),1.9521(dq,J1=6.80Hz,J2=5.84Hz,1H),2.0427(ddt,J=6.4Hz,J=13.36Hz,J=5.12Hz,1H),2.1486(ddt,J=6.40Hz,J=13.36Hz,J=5.12Hz,1H),2.2621(m,1H),2.8394(m,2H),2.9308(t,J=7.44Hz,2H),3.1147(dd,J=6.24Hz,J=13.04Hz,2H),3.1518(m,2H),3.1807(dd,J=6.80Hz,J=6.88Hz,2H),3.5514(dt,J=7.52Hz,J=16.82Hz,1H),3.7600(dt,J=7.52Hz,J=16.82Hz,1H),3.8745(d,2H),3.9968(d,2H),4.0249(dd,J1=6.32Hz,J2=11.52Hz,1H),4.0741(d,J=6.64Hz,1H),4.2167(d,J=7.12Hz,1H),4.2259(t,J=7.12Hz,1H),4.2355(t,J=7.12Hz,1H),4.3038(q,J=4.40Hz,1H),4.3567(t,J=6.80Hz,1H),4.5876(dd,J1=5.36Hz,J2=7.28Hz,1H)。
实验例1 评价Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)的抗血栓活性
将SD雄性大鼠(180-220g),随机分组,每组15只,静悉饲养一天,停止喂养过夜。经灌胃给予Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)的生理盐水溶液(剂量为100nmol/kg)或阿司匹林的生理盐水溶液(剂量为167μmol/kg)或生理盐水(剂量为10ml/kg)30min之后,大鼠用20%乌来糖的生理盐水溶液麻醉,之后手术。分离大鼠的右颈动脉和左颈静脉,将准确称重的丝线置于旁路插管,管的一端插入左静脉,另一端管插入右侧动脉并注射0.2mL肝素钠抗凝。使得血流从右侧动脉流经旁路插管进入左侧静脉,15min之后取出附有血栓的丝线称量,计算血液循环前后丝线的重量,得到的血栓重以表示并代表抗血栓活性,作t检验。数据列入表1。结果表明口服100nmol/kg化合物Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)能有效地抑制血栓形成。
表1 100nmol/kg Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)的抗栓活性
n=10,阿司匹林剂量167μmol/kg,口服给药,十肽给药剂量为100nmol/kg;a)表示与NS相比,p<0.01,b)与阿司匹林比,p>0.05。
实验结果表明:对浓度为100nmol/kg,十肽的血栓湿重为13.29±3.00mg,与生理盐水相比有显著性差异(28.56±4.12mg,p<0.01),十肽具有一定的抗栓活性。与阳性对照阿司匹林比较,p>0.05,无差异,活性相当,阳性对照的血栓湿重为12.97±2.48mg。
实验例2 评价Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)的溶血栓活性
SD大鼠(雄性,200±20g)按1200mg/kg的剂量腹腔注射乌拉坦生理盐水溶液进行麻醉。麻醉大鼠后将其仰卧位固定,分离其右颈总动脉,近心端处夹住动脉夹,将近心端及远心端分别穿入手术线,远心端的手术线结扎,远心端插管,将动脉夹松开,取出约1mL动脉血,置于1mL离心管中。往垂直固定的橡胶管(长15mm,内径2.5mm,外径5.0mm,管底用胶塞密封,para膜封紧)内注入0.1ml大鼠动脉血,随后在管内迅速插入一支不锈钢材质的血栓的固定螺栓(血栓固定螺旋用直径为0.2mm的不锈钢丝绕成,螺旋部分长10mm,内含15个螺圈,螺圈的直径为1.0mm,托柄与螺旋相连,长约7.0mm,呈问号型)。血液凝固45min后,从玻璃管中小心取出被血栓包裹的血栓固定螺旋,精确称其重量。
旁路插管由三部分构成,中间段为长60.0mm,内径3.5mm的聚乙烯胶管;两端均为长100.0mm,内径1.0mm,外径2.0mm的相同的聚乙烯管,该管一端拉成尖管,长约10.0mm(用于插入大鼠颈动脉及静脉),外径为1.0mm,其另一端的外部套一段长为7.0mm,外径为3.5mm的聚乙烯管(用于插入中段的聚乙烯胶管内),3段管的内壁均需要硅烷化(1%的硅油乙醚溶液)。将血栓包裹的血栓固定螺旋置于中段聚乙烯胶管内,胶管的另外两端分别与两根聚乙烯的加粗端相套,保证在循环的过程中不会漏血。用注射器通过尖管端将管中注满肝素生理盐水溶液(50IU/kg),排除气泡,备用。
分离大鼠的左颈外静脉,近心端和远心端分别穿入手术线,结扎远心端的血管,在暴露的左颈外静脉上剪一小口,将上述制备好的旁路管道尖管由小口插入左颈外静脉开口处,同时远离旁路管中段(含精确称量的血栓固定螺旋)内血栓固定螺旋。用注射器通过另一端的尖管注入准确量的肝素钠的生理盐水溶液(50IU/kg),此时注射器不要撤离聚乙烯管,用动脉夹夹住注射器与聚乙烯管之间的软管。在右颈总动脉的近心端用动脉夹止血,结扎远心端,在离动脉夹不远处将右颈总动脉剪一小口,从聚乙烯管的尖部拔出注射器,将聚乙烯管的尖部插入动脉斜口的近心端。旁路管道的两端均用4号手术缝线将动静脉固定。
用头皮针将生理盐水(3mL/kg),尿激酶的生理盐水溶液(20 000IU/kg)或The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys(十肽)的生理盐水溶液(剂量为100nmol/kg)通过旁路管的中段(含精确称重的血栓固定螺旋),刺入远离血栓固定螺旋的近静脉处,打开动脉夹,使血流通过旁路管道从动脉流向静脉。将注射器中的溶液缓慢注入血液,通过血液循环,按静脉-心脏-动脉的顺序作用于螺旋的血栓上。血液循环1h之后,从旁路管道中取出固定血栓的螺旋,精确称量。计算每只大鼠旁路管道中固定血栓的螺旋血液循环前后血栓的重量差,以均值表示并代表溶血栓活性,作t检验。数据列入表2。结果表明100nmol/kg Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)能有效地溶解形成的血栓。
表2 100nmol/kg Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)溶栓活性
n=10,尿激酶剂量为20000IU/kg;化合物给药剂量为1nmol/kg,a)与生理盐水相比,p<0.01,b)与尿激酶比,p>0.05。
实验结果表明:对浓度为100nmol/kg的十肽的血栓减重为34.69±6.36mg,与生理盐水比较有显著性差异(27.40±3.20mg,p<0.01),与阳性对照尿激酶比较,p>0.05无差异,活性相当,阳性对照尿激酶的血栓减重为40.14±5.43mg。
实验例3 评价Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)对缺血性中风大鼠的治疗作用
在雄性SD大鼠(体重300±20g)的颈部正中部竖直开约2cm长切口,沿胸锁乳突肌内侧缘分离出右颈总动脉、颈外动脉及颈内动脉。用无创动脉夹分别夹闭颈内动脉开口处和颈总动脉近心端,结扎颈外动脉的远心端,在颈外动脉剪一小口,松开颈总动脉近心端的动脉夹,取10μL血,之后再用无创动脉夹夹闭颈总动脉的近心端。
将取得的10μL血放置在1mL EP管中常温放置30分钟使血液凝固,然后转移至-20℃冰箱中放置1小时,使血液凝块结实。大鼠用10%水合氯醛腹腔注射麻醉,剂量为400mg/kg。取出血液凝块,加入1mL生理盐水,用钢铲把血液凝块捣成大小均一的细小血栓块,制备细小血栓的悬液并转移至1mL注射器内。松开颈总动脉近心端的动脉夹,将1mL血栓混悬液缓慢从大鼠颈外动脉向近心端经过颈内动脉注入大鼠的大脑,然后结扎颈外动脉近心端,打开颈内动脉和颈总动脉处得动脉夹,恢复血流。等待苏醒。大鼠苏醒24小时后按Zealonga方法评定神经功能缺损程度。0分表示无任何神经功能缺失体征、1分表示未损伤侧前肢不能伸展、2分表示向未损伤侧行走、3分表示向未损伤侧转圈成追尾状行走、4分表示意识障碍无自主行走、5分表示死亡。大鼠经尾静脉每天注射1次Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽),剂量为100nmol/kg。连续注射6天,每天评分。结果列入表3。数据表明Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)连续治疗6天除可使2只脑缺血24小时的大鼠神经生物学评分为0分,还可将8只脑缺血24小时神经生物学评分为2分和3分的大鼠改善为1分,因为不像已经公开的化合物首次剂量需要5μmol/kg,后5次维持剂量需要2μmol/kg,Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)6次剂量均为100nmol/kg。这样一来,首次剂量和维持剂量分别降低了50倍和20倍。
表3 Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The(十肽)连续治疗6天对脑缺血24小时大鼠神经生物学评分的影响
n=10。
Claims (5)
1.一种十肽,氨基酸序列为Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The。
2.权利要求1所述十肽的制备方法,该方法包括:
(1)Boc-Asp(OMe)与Val-OBzl偶联得到Boc-Asp(OMe)-Val-OBzl;
(2)Boc-Asp(OMe)-Val-OBzl在4N氯化氢的乙酸乙酯溶液中得Asp(OMe)-Val-OBzl;(3)Boc-Gly与Asp(OMe)-Val-OBzl偶联得到Boc-Gly-Asp(OMe)-Val-OBzl;
(4)Boc-Gly-Asp(OMe)-Val-OBzl在4N氯化氢的乙酸乙酯溶液中得到Gly-Asp(OMe)-Val-OBzl;
(5)Boc-Arg(Tosh)与Gly-Asp(OMe)-Val-OBzl偶联得到Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl;
(6)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl在Pd/C和H2的作用下得到Boc-Arg(Tosh)-Gly-Asp(OMe)-Val;
(7)Boc-Ala与Lys(Z)-OBzl偶联得到Boc-Ala-Lys(Z)-OBzl;
(8)Boc-Ala-Lys(Z)-OBzl在4N氯化氢的乙酸乙酯溶液中得到Ala-Lys(Z)-OBzl;
(9)Boc-Pro与Ala-Lys(Z)-OBzl偶联得到Boc-Pro-Ala-Lys(Z)-OBzl;
(10)Boc-Pro-Ala-Lys(Z)-OBzl在4N氯化氢的乙酸乙酯溶液中得到Pro-Ala-Lys(Z)-OBzl;
(11)Boc-Arg(NO2)与Pro-Ala-Lys(Z)-OBzl偶联得到Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(12)Boc-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl在4N氯化氢的乙酸乙酯溶液中得到Arg(NO2)-Pro-Ala-Lys(Z)-OBzl
(13)Boc-Gly与Arg(NO2)-Pro-Ala-Lys(Z)-OBzl偶联得到Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl;
(14)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl在2N NaOH溶液的作用下得到Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z);
(15)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)与The-OBzl偶联得到Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl;
(16)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl在4N氯化氢的乙酸乙酯溶液中得到Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl;
(17)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val与Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl偶联得到Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl;
(18)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-OBzl在2N NaOH的甲醇溶液中得到Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The;
(19)Boc-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The在三氟乙酸或三氟甲磺酸=4:1溶液中得到Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The。
3.权利要求1所述十肽Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The在制备抗血栓药物中的应用。
4.权利要求1所述十肽Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The在制备溶血栓药物中的应用。
5.权利要求1所述十肽Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys-The在制备缺血性中风药物中的应用。
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