莨菪烷类化合物拮抗M_3受体、抑制中性粒细胞弹性蛋白酶活性的研究
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摘要
目的·设计、合成5个新莨菪烷类化合物,测试其拮抗M3受体、抑制中性粒细胞弹性蛋白酶(NE)的活性,初步分析2种活性的构效关系。方法·对莨菪烷母核的C-3α位、N原子进行结构改造,以3α-羟基莨菪烷(A0)为起始物,合成A1~A3、B1、C1。选取豚鼠气道环为测试样本,通过离体组织功能实验,测试目标物对M3受体的拮抗活性。利用NE催化底物PGlu-Pro-ValPNA的水解反应,测定有色产物硝基苯胺(PNA)的吸光度值[D(405 nm)],获得目标物对NE的抑制活性。结果·5个新化合物对M3受体都具有较强的拮抗作用,其中A2的拮抗活性最大,拮抗参数pA_2(M_3)=9.004;并且A2对NE具有较明显的抑制作用(抑制率Y_(A2)=20.29%)。结论·在莨菪烷母核的C-3α位引入强吸电子基团磺酰基和大体积疏水基团时,有利于同时提高化合物拮抗M_3受体、抑制NE的活性。
Objective · To design and synthesize five new tropane compounds, and test their antagonistic activity against M_3 receptor and inhibition activity to neutrophil elastase(NE), of which the structure-activity relationship were preliminarily investigated. Methods · The five compounds, A1-A3, B1 and C1, were prepared with 3α-hydroxy-tropane(A0) as the starting material by modifying the structure in C-3α position and N atom on the tropane skeleton. The antagonistic activity of the compounds to muscarinic M_3 receptors on tracheal rings of guinea pigs was evaluated by functional assays in vitro. The hydrolysis of PGlu-Pro-Val-PNA as substrate was catalyzed by NE to get colorful nitroaniline(PNA). The NE inhibition activity of the tropane compounds was obtained by determining the absorbance [(D(405 nm)] of PNA. Results · The five new tropane compounds generated strong antagonistic activity against M3 receptors. Among them, A2 had the greatest activity [antagonistic parameter pA_2(M_3)=9.004], and elicited obvious inhibitory effect to NE(inhibition ratio Y_(A2)=20.29%). Conclusion · Introducing strong electron-attraction group, such as sulfuryl and hydrophobic group with large volume into C-3α position on the tropane skeleton can improve the M_3 receptor antagonistic activity as well as the NE inhibition activity.
Objective · To design and synthesize five new tropane compounds, and test their antagonistic activity against M_3 receptor and inhibition activity to neutrophil elastase(NE), of which the structure-activity relationship were preliminarily investigated. Methods · The five compounds, A1-A3, B1 and C1, were prepared with 3α-hydroxy-tropane(A0) as the starting material by modifying the structure in C-3α position and N atom on the tropane skeleton. The antagonistic activity of the compounds to muscarinic M_3 receptors on tracheal rings of guinea pigs was evaluated by functional assays in vitro. The hydrolysis of PGlu-Pro-Val-PNA as substrate was catalyzed by NE to get colorful nitroaniline(PNA). The NE inhibition activity of the tropane compounds was obtained by determining the absorbance [(D(405 nm)] of PNA. Results · The five new tropane compounds generated strong antagonistic activity against M3 receptors. Among them, A2 had the greatest activity [antagonistic parameter pA_2(M_3)=9.004], and elicited obvious inhibitory effect to NE(inhibition ratio Y_(A2)=20.29%). Conclusion · Introducing strong electron-attraction group, such as sulfuryl and hydrophobic group with large volume into C-3α position on the tropane skeleton can improve the M_3 receptor antagonistic activity as well as the NE inhibition activity.
引文
[1]Profita M,Bonanno A,Siena L,et al.Acetylcholine mediates the release of IL-8in human bronchial epithelial cells by a NFκB/ERK-dependent mechanism[J].Eur J Pharmacol,2008,582(1-3):145-153.
[2]Mackay A,Al-Haddad M.Acute lung injury and acute respiratory distress syndrome[J].Contin Educ Anaesth Crit Care Pain,2009,9(5):152-156.
[3]Cazzola M.Aclidinium bromide,a novel long-acting muscarinic M3 antagonist for the treatment of COPD[J].Curr Opin Investig Drugs,2009,10(5):482-490.
[4]von Nussbaum F,Li VM.Neutrophil elastase inhibitors for the treatment of(cardio)pulmonary diseases:into clinical testing with pre-adaptive pharmacophores[J].Bioorg Med Chem Lett,2015,25(20):4370-4381.
[5]Lu S,Parekh DD,Kuznetsova O,et al.An oral selective M3 cholinergic receptor antagonist in COPD[J].Eur Respir J,2006,28(4):772-780.
[6]王嘉,孙武装,于卫芳,等.慢性阻塞性肺疾病血清中性粒细胞弹性蛋白酶和αl-抗胰蛋白酶的检测及其意义[J].国际呼吸杂志,2011,31(17):1285-1289.
[7]Yoshioka A,Betsuyaku T,Nishimura M,et al.Excessive neutrophil elastase in bronchoalveolar lavage fluid in subclinical emphysema[J].Am J Respir Crit Care Med,1995,152(6 Pt 1):2127-2132.
[8]揭志军,杨文兰,蔡映云,等.蛋白酶-抗蛋白酶失衡在内毒素诱发急性肺损伤中的作用[J].中国危重病急救医学,2000,12(1):10-14.
[9]Kawabata K,Hagio T,Matsuoka S.The role of neutrophil elastase in acute lung injury[J].Eur J Pharmacol,2002,451(1):1-10.
[10]Lee WL,Downey GP.Leukocyte elastase:physiological functions and role in acute lung injury[J].Am J Respir Crit Care Med,2001,164(5):896-904.
[11]Betsuyaku T,Nishimura M,Takeyabu K,et al.Decline in FEV1 in community-based older volunteers with higher levels of neutrophil elastase in bronchoalveolar lavage fluid[J].Respiration,2000,67(3):261-267.
[12]Sng JJ,Prazakova S,Thomas PS,et al.MMP-8,MMP-9 and neutrophil elastase in peripheral blood and exhaled breath condensate in COPD[J].COPD,2017,14(2):238-244.
[13]Wang L,Zhang B,Li Z,et al.Budesonide mitigates pathological changes in animal model of COPD through reducing neutrophil elastase expression[J].Int J Clin Exp Med,2015,8(4):5227-5235.
[14]欧美贤,史一鸣,刘慧中,等.莨菪烷类化合物的合成及其对M3受体的拮抗活性[J].上海交通大学学报(医学版),2011,31(7):909-912.
[15]刘慧中,欧美贤,严忠红,等.莨菪烷衍生物的合成及其对大鼠气管的拮抗活性和组织选择性[J].上海交通大学学报(医学版),2012,32(1):27-31.
[16]Tyagi SC,Simon SR.Interaction of neutrophil elastase with hydrophobic polyanionic chelators[J].Biochem Cell Biol,1991,69(9):624-629.
[17]Hsu PS,Izaki S,Hibino T,et al.Elastase activity in granulomatous inflammation in experimental murine leprosy[J].Exp Mol Pathol,1986,45(1):84-92.
[18]沈定树.组织液中粒细胞弹性蛋白酶的测定法[J].国际检验医学杂志,1991,12(4):189.
[2]Mackay A,Al-Haddad M.Acute lung injury and acute respiratory distress syndrome[J].Contin Educ Anaesth Crit Care Pain,2009,9(5):152-156.
[3]Cazzola M.Aclidinium bromide,a novel long-acting muscarinic M3 antagonist for the treatment of COPD[J].Curr Opin Investig Drugs,2009,10(5):482-490.
[4]von Nussbaum F,Li VM.Neutrophil elastase inhibitors for the treatment of(cardio)pulmonary diseases:into clinical testing with pre-adaptive pharmacophores[J].Bioorg Med Chem Lett,2015,25(20):4370-4381.
[5]Lu S,Parekh DD,Kuznetsova O,et al.An oral selective M3 cholinergic receptor antagonist in COPD[J].Eur Respir J,2006,28(4):772-780.
[6]王嘉,孙武装,于卫芳,等.慢性阻塞性肺疾病血清中性粒细胞弹性蛋白酶和αl-抗胰蛋白酶的检测及其意义[J].国际呼吸杂志,2011,31(17):1285-1289.
[7]Yoshioka A,Betsuyaku T,Nishimura M,et al.Excessive neutrophil elastase in bronchoalveolar lavage fluid in subclinical emphysema[J].Am J Respir Crit Care Med,1995,152(6 Pt 1):2127-2132.
[8]揭志军,杨文兰,蔡映云,等.蛋白酶-抗蛋白酶失衡在内毒素诱发急性肺损伤中的作用[J].中国危重病急救医学,2000,12(1):10-14.
[9]Kawabata K,Hagio T,Matsuoka S.The role of neutrophil elastase in acute lung injury[J].Eur J Pharmacol,2002,451(1):1-10.
[10]Lee WL,Downey GP.Leukocyte elastase:physiological functions and role in acute lung injury[J].Am J Respir Crit Care Med,2001,164(5):896-904.
[11]Betsuyaku T,Nishimura M,Takeyabu K,et al.Decline in FEV1 in community-based older volunteers with higher levels of neutrophil elastase in bronchoalveolar lavage fluid[J].Respiration,2000,67(3):261-267.
[12]Sng JJ,Prazakova S,Thomas PS,et al.MMP-8,MMP-9 and neutrophil elastase in peripheral blood and exhaled breath condensate in COPD[J].COPD,2017,14(2):238-244.
[13]Wang L,Zhang B,Li Z,et al.Budesonide mitigates pathological changes in animal model of COPD through reducing neutrophil elastase expression[J].Int J Clin Exp Med,2015,8(4):5227-5235.
[14]欧美贤,史一鸣,刘慧中,等.莨菪烷类化合物的合成及其对M3受体的拮抗活性[J].上海交通大学学报(医学版),2011,31(7):909-912.
[15]刘慧中,欧美贤,严忠红,等.莨菪烷衍生物的合成及其对大鼠气管的拮抗活性和组织选择性[J].上海交通大学学报(医学版),2012,32(1):27-31.
[16]Tyagi SC,Simon SR.Interaction of neutrophil elastase with hydrophobic polyanionic chelators[J].Biochem Cell Biol,1991,69(9):624-629.
[17]Hsu PS,Izaki S,Hibino T,et al.Elastase activity in granulomatous inflammation in experimental murine leprosy[J].Exp Mol Pathol,1986,45(1):84-92.
[18]沈定树.组织液中粒细胞弹性蛋白酶的测定法[J].国际检验医学杂志,1991,12(4):189.