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CN110946861A - 一种对腺苷a1受体具有选择性和拮抗活性的分子 - Google Patents

一种对腺苷a1受体具有选择性和拮抗活性的分子 Download PDF

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CN110946861A
CN110946861A CN201910547235.5A CN201910547235A CN110946861A CN 110946861 A CN110946861 A CN 110946861A CN 201910547235 A CN201910547235 A CN 201910547235A CN 110946861 A CN110946861 A CN 110946861A
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adenosine
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林建平
李冬梅
魏宇
王目阔
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Abstract

本发明提供1种选择性腺苷A1受体拮抗剂。本发明通过整合现有的腺苷A1受体配体和活性数据、虚拟筛选和体外生物实验方法，首次找到具有A1/A2A选择性的新型腺苷A1受体拮抗剂3829‑0650(3‑Quinolinecarbonitrile，2‑amino‑4‑(1，3‑benzodioxol‑5‑yl)‑5，6，7，8‑tetrahydro‑)。该化合物与腺苷A1受体结合(binding assay)的IC50为0.16μM，Ki为0.074μM；与腺苷A2A受体结合的IC50大于100μM，Ki大于100μM。进一步的功能性实验(A1antagonist cAMP assay)显示其对腺苷A1受体发生拮抗的IC50为0.418μM。

Description

一种对腺苷A1受体具有选择性和拮抗活性的分子
技术领域
本发明涉及小分子药物领域，更具体而言，涉及一种选择性腺苷A1受体拮抗剂。
背景技术
腺苷是多种生理活动中普遍存在的调节剂，特别是在心血管和神经系统中，通过与特异性细胞表面受体的相互作用，调节多种生理功能。已知的腺苷受体有四种亚型，分别为A1、A2A、A2B、A3，属于G蛋白偶联受体家族。腺苷A1和A3受体通过与抑制腺苷酸环化酶的G蛋白偶联来下调细胞cAMP水平，而腺苷A2A和A2B受体通过与活化腺苷酸环化酶的G蛋白偶联上调细胞内的cAMP水平。通过这些受体，腺苷调控广泛的生理功能。
腺苷A1受体是一个有吸引力的药理靶点，在整个大脑中都有表达，包括皮质、海马和纹状体。其拮抗剂可作为肾脏保护剂、认知促进剂、以及平喘剂和中枢神经系统药物。腺苷A1受体拮抗剂在炎性疾病中起到潜在的治疗作用，在哮喘和炎症的啮齿动物模型中已经显示出其功效。有报告显示腺苷A1拮抗剂能够降低梗塞面积，在高血压、充血性心力衰竭等疾病中具有治疗潜能。另外，腺苷A1受体参与调节肠道运动，腺苷A1受体的激活会导致肠梗阻推进运动活性的抑制，拮抗剂能够阻断A1受体从而恢复肠道正常的运动功能，并不导致腹泻，腺苷A1受体拮抗剂是治疗各种结肠功能运动性综合征(包括便秘和术后肠梗阻)的潜在治疗策略。
因此选择性腺苷A1受体拮抗剂的发现对于因腺苷A1受体高表达或活性过高所导致的相关疾病的治疗具有重大意义。
发明内容
发明人建立了随机森林(random forest)分类模型、基于能量的药效团(e-pharmacophore)模型、分子对接模型，并逐级利用这些模型在Chemdiv数据库中筛选得到化合物3829-0650(3-Quinolinecarbonitrile，2-amino-4-(1，3-benzodioxol-5-yl)-5，6，7，8-tetrahydro-)，体外生物实验发现其具有腺苷A1受体拮抗活性并具有较好的A1/A2A选择性。化合物3829-0650的腺苷A1受体结合实验(binding assay)的IC50为0.16μM，Ki为0.074μM；其腺苷A2A受体结合实验的IC50大于100μM，Ki大于100μM。化合物3829-0650对腺苷A1和A2A受体的Ki比值小于0.00074，表明该化合物对腺苷A1受体具有选择性。化合物3829-0650腺苷A1受体功能实验(A1 antagonist cAMP assay)的IC50为0.418μM，证明该化合物具有较高的腺苷A1受体拮抗活性。
本发明的化合物3829-0650结构如附图1所示：
3829-0650分子式：C17H15N3O2。
3829-0650分子量：293.330。
附图说明
附图1.化合物3829-0650的结构式；
附图2.结合实验中化合物3829-0650对腺苷A1受体的抑制率曲线；
附图3.结合实验中化合物3829-0650对腺苷A2A受体的抑制率曲线；
附图4.功能实验中化合物3829-0650对腺苷A1受体的抑制率曲线；
具体实施方式
为了理解本发明，下面以实施例进一步说明本发明，但不意于限制本发明的保护范围。
本研究利用多级虚拟筛选技术，利用已有的腺苷A1受体拮抗剂数据构建随机森林(random forest)，并利用该模型对Chemdiv数据库进行第一级筛选；然后利用腺苷A1受体的晶体结构(PDBID：5N2S)构建基于能量的药效团模型(e-pharmacophore)，并进行第二级筛选；最后利用腺苷A1受体的晶体结构进行基于分子对接的第三级筛选。将第三级筛选得到的化合物3829-0650分别进行结合活性测试(A1/A2A binding assay)和功能活性测试(A1antagonist cAMP assay)。
化合物3829-0650结合活性测试实验过程：
(1)A1 Binding Assay：
试剂配制
反应缓冲液
500mL体积用HCl将pH调到7.4
Name Weight Final Conc
Tris-base 3.03g 50mM
MgCl<sub>2</sub> 0.476g 10mM
EDTA 1mL 1mM
Adenosine Deaminase 500μg 1μg/mL
洗液
体积是2L，配置成10X洗液用HCl将pH调到7.4
Name Weight(2L) Final Conc
Tris-base 121.14g 500mM
NaCl 180g 1.54M
用ddH2O按1∶10比例稀释成1X洗液后再使用。
孵育UNIFILTER-96GF/B缓冲液
Name Weight ddH<sub>2</sub>O Final Conc
PEI 0.5mL 100mL 0.5％
化合物稀释
a)化合物储存浓度为20mM溶于DMSO中，在-20℃中储存。
b)阳性化合物：DPCPX。
c)化合物在384圆底板子中稀释，化合物的起始浓度为10μM，3倍稀释，10个点，0.5％DMSO作为阴性对照，100uM DPCPX作为阳性对照。
阳性化合物稀释如下：
[Required]μM [Stock](100X)mM Dilution
10 2 6μl 20mM cpd+54μL DMSO
3.33333 0.6667 20μL of 2mM cpd+40μL DMSO
1.11111 0.2222 20μL of 0.6667mM cpd+40μL DMSO
0.37037 0.0741 20μL of 0.2222mM cpd+40μL DMSO
0.12346 0.0247 20μL of 0.0741mM cpd+40μL DMSO
0.04115 0.0082 20μL of 0.0247mM cpd+40μL DMSO
0.01372 0.0027 20μL of 0.0082mM cpd+40μL DMSO
0.00457 0.0009 20μL of 0.0027mM cpd+40μL DMSO
0.00152 0.0003 20μL of 0.0009mM cpd+40μL DMSO
0.00051 0.0001 20μL of 0.0003mM cpd+40μL DMSO
negative control 40μL DMSO
Positive control 10 20μL 20mM DPCPX+20μL DMSO
利用Echo550将250nL稀释的化合物转移到Opti-plate中，两个复孔，最终0.5％DMSO。
实验过程
a)总反应体系是50μL，用Echo550加入250nL化合物(0.5％DMSO)到Opti-plate中，封口膜封口。
b)配制膜、[3H]-DPCPX与反应缓冲液的混合液：每个孔中加入0.5μL A1膜(1U/μL)和[3H]-DPCPX(终浓度2.5nM)和50μL反应缓冲液到96孔板中，600rpm震荡5min混匀。
c)在25℃孵育50min。
d)用0.5％PEI处理UNIFILTER-96GF/B板，每孔加入150uL的0.5％PEI，在4℃预孵育1.5小时。
e)用Universal Harvester洗UNIFILTER-96GF/B板2次，每次50mL洗液。
f)将孵育后的反应液转移到UNIFILTER-96GF/B板上，每孔加入900μL洗液，用Universal Harvester冲洗4次，洗后的UNIFILTER-96GF/B板55℃烘干10分钟。
g)每孔加入40μL ULTIMA GOLD闪烁液，使用Top Count读数。
数据分析
a)Kd值通过GraphPad Prism 6软件作图获得。.
b)IC50通过使用Xlfit 5.3.1分析数据获得，X轴是化合物浓度，Y轴是CPM值。
化合物IC50的拟合曲线：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：Log of cpd concentration
Y：Percent inhibition(％inh)
Top and Bottom：Plateaus in same units as Y
logIC50：same log units as X
HillSlope：Slope factor or Hill slope
c)Ki＝IC50/(1+(c)/Kd)
(2)A2A Binding Assay
试剂配制
反应缓冲液
500mL体积用HCl将pH调到7.4
Name Weight Final Conc
Tris-base 3.03g 50mM
MgCl<sub>2</sub> 0.476g 10mM
EDTA 1mL 1mM
Adenosine Deaminase 500μg 1μg/mL
洗液
体积是2L，配置成10X洗液用HCl将pH调到7.4
Name Weight(2L) Final Conc
Tris-base 121.14g 500mM
NaCl 180g 1.54M
用ddH2O按1∶10比例稀释成1X洗液后再使用。
孵育UNIFILTER-96GF/B缓冲液
Name Weight ddH<sub>2</sub>O Final Conc
PEI 0.5mL 100mL 0.5％
化合物稀释
d)化合物储存浓度为20mM溶于DMSO中，在-20℃中储存。
e)阳性化合物：ZM-241385。
f)化合物在384圆底板子中稀释，化合物的起始浓度为1μM，3倍稀释，10个点，1％DMSO作为阴性对照，10uM ZM-241385作为阳性对照。
阳性化合物稀释如下：
[Required]μM [Stock](100X)mM Dilution
1 0.1 1μl 20mM cpd+199μL DMSO
0.333333 0.0333 20μL of 30mM cpd+40μL DMSO
0.111111 0.0111 20μL of 10mM cpd+40μL DMSO
0.037037 0.0037 20μL of 3.33mM cpd+40μL DMSO
0.012346 0.00123 20μL of 1.11mM cpd+40μL DMSO
0.004115 0.00041 20μL of 0.37mM cpd+40μL DMSO
0.001372 0.000137 20μL of 0.12mM cpd+40μL DMSO
0.000457 0.000045 20μL of 0.041mM cpd+40μL DMSO
0.000152 0.000015 20μL of 0.0137mM cpd+40μL DMSO
0.00005 0.000005 20μL of 0.0046mM cpd+40μL DMSO
negative control 40μL DMSO
Positive control 1 2μL 20mM ZM-241385+38μL DMSO
转移5μL稀释后的化合物到96深孔板中，2个复孔，1％DMSO。
实验过程
a)总反应体系为500μL，每个孔中加入100μL的反应缓冲液和5μL稀释后的化合物(1％DMSO)到96深孔板中。
b)配制膜与反应缓冲液的混合液：每个孔中加入1μL A2A膜(1U/μL)和300μL反应缓冲液到96孔板中，600rpm震荡5min混匀。
c)每个孔中加入100μL的反应缓冲液和[3H]-ZM 241385(终浓度为0.5nM)混合液到反应体系中，600rpm震荡5min混匀。
d)在27℃孵育1.5h。
e)用0.5％PEI处理UNIFILTER-96GF/B板，每孔加入150uL的0.5％PEI，在4℃预孵育1.5小时。
f)用Universal Harvester洗UNIFILTER-96GF/B板2次，每次50mL洗液。
g)将孵育后的反应液转移到UNIFILTER-96GF/B板上，每孔加入900μL洗液，用Universal Harvester冲洗4次，洗后的UNIFILTER-96GF/B板55℃烘干10分钟。
h)每孔加入40μL ULTIMA GOLD闪烁液，使用Top Count读数。
数据分析
d)Kd值通过GraphPad Prism 6软件作图获得。.
e)IC50通过使用Xlfit 5.3.1分析数据获得，X轴是化合物浓度，Y轴是CPM值。
化合物IC50的拟合曲线：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：Log of cpd concentration
Y：Percent inhibition(％inh)
Top and Bottom：Plateaus in same units as Y
logIC50：same log units as X
HillSlope：Slope factor or Hill slope
f)K1＝IC50/(1+(c)/Kd)
化合物3829-0650功能活性测试(A1 antagonist cAMP assay)实验过程：
细胞培养和接种：
1.CHO-K1-Adenosine A1稳定细胞株培养于37℃，5％CO2的细胞完全培养基中。
2.实验缓冲液：1X HBSS，0.1％BSA，20mM HEPES，100nM IBMX。
3.细胞接种：将细胞重悬于实验缓冲液中，每孔接种8000个细胞于384孔(6007680-50，PE)检测板中。
化合物拮抗剂活性检测：
1.用实验缓冲液制备8X待测化合物工作液(化合物编号：3829-0650)。
2.添加2.5μl 8X待测化合物工作液至上述384孔检测板中，于37℃孵育10分钟。
3.用实验缓冲液制备forskolin(8μM)和NECA(40nM)混合物。
4.添加2.5μl forskolin和NECA的混合物至检测板中，于37℃孵育30min。
5.用裂解缓冲液制备20X cAMP-d2和20X Anti-cAMP-Eu3+检测试剂。
6.向检测板中加入10μl cAMP-d2，随后加入10μl Anti-cAMP-Eu3+。
7.将检测板于室温孵育1小时。
8.利用Envision 2104酶标仪收集波长为665nm和615nm的HTRF信号。
数据分析：
●Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；
●CVMax＝(SDMax/MeanMax)*100％；
●CVMin＝(SDMin/MeanMin)*100％；
●S/B＝Singal/Background；
●使用GraphPad的非线性拟合公式计算化合物EC50/IC50：
●Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50/IC50-X)*HillSlope))
X：log of compound concentration；Y：％Activation or Inhibition％。

Claims (1)

1.小分子化合物在制备腺苷A1受体拮抗剂药物方面的用途，所述小分子化合物为：3-Quinolinecarbonitrile，2-amino-4-(1，3-benzodioxol-5-yl)-5，6，7，8-tetrahydro-，
Figure FSA0000184811220000011
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NATHAN A. LACK等: "Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

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