CN109745317A - 腺苷受体激动剂的应用及评价方法及治疗膀胱泌尿功能障碍的药物 - Google Patents

腺苷受体激动剂的应用及评价方法及治疗膀胱泌尿功能障碍的药物 Download PDF

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CN109745317A
CN109745317A CN201711093188.9A CN201711093188A CN109745317A CN 109745317 A CN109745317 A CN 109745317A CN 201711093188 A CN201711093188 A CN 201711093188A CN 109745317 A CN109745317 A CN 109745317A
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Abstract

本发明公开了一种腺苷受体激动剂在制备治疗哺乳动物膀胱泌尿功能障碍的药物中的应用，可以有效的增加膀胱容量和减少排尿频率，以及一种评价腺苷受体激动剂调节哺乳动物膀胱泌尿功能障碍的方法。

Description

腺苷受体激动剂的应用及评价方法及治疗膀胱泌尿功能障碍 的药物
技术领域
本发明涉及腺苷受体激动剂在制备治疗膀胱泌尿功能障碍的药物中的应用,及评价腺苷受体激动剂调节哺乳动物膀胱泌尿功能障碍的方法。
背景技术
膀胱泌尿功能障碍如尿频，尿急，夜尿，尿痛，膀胱过度活跃综合症，尿失禁，间质性膀胱炎，药物性膀胱炎(氯氨酮膀胱炎)等影响至少50％以上的>40岁人群。目前治疗手段有限，包括：控制液体摄人，药物控制，使用成人尿不湿，以及手术治疗。就药物而言，目前主要有：1.一线抗胆碱药，但目前口服剂型疗效有限且副作用大(大多最后放弃使用)；2. 近来有β3受体激动剂用于治疗，有一定疗效但副作用大；3.FDA最近批准了BOTOX用于膀胱局部注射治疗，通过局部麻痹膀胱神经末梢以治疗膀胱过度活跃。
腺苷受体可以分为A1，A2a，A2b，和A3四个亚单位。关于腺苷受体信号以及它的激动剂如何调节在体膀胱排尿功能，以及以此作为可能临床用药治疗泌尿功能障碍尚未见报道。
另外，目前在泌尿领域的研究也存在很大的误区：机械的把降低膀胱的活跃程度和降低膀胱平滑肌的收缩力等同起来。其实膀胱平滑肌收缩力的降低有可能降低膀胱活跃程度，但也可能直接导致尿潴留或排尿不尽，从而引起膀胱排尿频次增多容量减小，反而表现为膀胱过度活跃。因此药物在体外对膀胱平滑肌的收缩力的调节不能直接用来推测其在在体对膀胱泌尿功能的调节作用。另外，在储尿期膀胱平滑肌需要在保持一定收缩力的条件下缓慢地舒张，因此药物在体外对膀胱平滑肌的收缩力的抑制作用也不一定表明在体内储尿期的膀胱的舒张。因此，药物对膀胱排尿功能的调节作用必须最后以在体的实验才能验证。基于这些错误的认识，目前对泌尿功能机理研究及药物的评价多侧重于细胞和组织水平，而缺少全面的评价体系。从而严重阻碍了对于相应药物调节泌尿功能的研究。
发明内容
针对上述现有的技术问题，本发明的目的就是提供一种可以应用在制备治疗膀胱泌尿功能障碍的药物中的腺苷受体激动剂。
本发明的另一个目的在于提供一种评价腺苷受体激动剂调节哺乳动物膀胱泌尿功能障碍的方法。
为达到上述目的，本发明采用以下技术方案：
腺苷受体激动剂在制备治疗膀胱泌尿功能障碍的药物中的应用,其中所述腺苷受体激动剂是式(I)的化合物：
其中：R1＝heteroaryl,or
R2＝OR’(R’＝H,hydroxyalkyl,cycloalkyl or CH3),or NHCOCH3。
优选的，所述膀胱为哺乳动物膀胱。
优选的，所述哺乳动物为人、鼠、猪、猫或狗。
优选的，所述腺苷受体为其亚单位A2b。
优选的，所述膀胱泌尿功能障碍包括尿频，尿急，夜尿，尿痛，膀胱过度活跃综合症，尿失禁，间质性膀胱炎，药物性膀胱炎。
优选的，所述腺苷受体激动剂是Bay 60-6583：
一种评价腺苷受体激动剂调节哺乳动物膀胱泌尿功能障碍的方法，该方法包括：
利用体外离体的平滑肌确定腺苷受体激动剂对哺乳动物膀胱平滑肌收缩力的调节作用；
敲除哺乳动物腺苷受体基因，以观察由此引起的哺乳动物膀胱功能改变；
给正常哺乳动物直接皮下注射腺苷受体激动剂以观察它在在体条件下对膀胱功能的调节作用，
所述腺苷受体激动剂是式(II)的化合物：
优选的，所述腺苷受体为其亚单位A2b基因。
优选的，所述哺乳动物为人、鼠、猪、猫或狗。
优选的，所述膀胱泌尿功能障碍包括尿频，尿急，夜尿，尿痛，膀胱过度活跃综合症，尿失禁，间质性膀胱炎，药物性膀胱炎。
本发明的有益效果：
本发明采用上述技术方案以后，可以有效的增加膀胱容量和减少排尿频率，因此可作为一有效的用于治疗泌尿功能障碍的药物。
附图说明
图1是Bay 60-6583选择性地抑制嘌呤介导的膀胱平滑肌收缩的实验数据图。
图2是腺苷A2b受体基因敲除导致小鼠膀胱功能过度活跃的实验数据图。
图3是Bay 60-6583注射减少排尿次数增加尿容量的实验数据图。
具体实施方式
本发明包括调节膀胱平滑肌的收缩力的方法，该方法包括为需要的哺乳动物注射有效剂量的腺苷受体激动剂，所述激动剂优选为Bay60-6583，所述腺苷受体为其亚单位A2b。
本发明还涉及一种评价A2b腺苷受体激动剂调节哺乳动物膀胱泌尿功能障碍的方法：
(1)利用体外离体的平滑肌确定A2b腺苷受体激动剂如Bay 60-6583对哺乳动物膀胱平滑肌收缩力的调节作用；
(2)敲除小鼠A2b腺苷受体基因，以观察由此引起的哺乳动物膀胱功能改变。
(3)给正常哺乳动物直接皮下注射A2b腺苷受体激动剂如Bay 60-6583以观察它在在体条件下对膀胱功能的调节作用。
以小鼠为实验对象，具体实验过程如下：
1、A2b腺苷受体激动剂如Bay 60-6583能选择性地抑制小鼠膀胱平滑肌的嘌呤性收缩力。
实验目的：为测试A2b腺苷受体激动剂如Bay 60-6583对膀胱平滑肌收缩力的影响，我们用肌电图测量离体肌条对Bay 60-6583的反应。
实验方法：12-16周大的雄性C57BL/6J小鼠的膀胱用于实验。去除内表皮以后的膀胱平滑肌被分成4条5-7毫米长和2-3毫米宽的肌条。肌条的一端通过6-0号丝线固定于架子上，另一端以6-0号丝线连至力传感器。肌条位于架子上的两个铂金电极之间并置于SI－MB4水浴系统中(World Precision Instruments,FL,USA)。肌条的力信号通过TBM 4M信号转换器转换成数字信号并被Powerlab放大通过Chart软件实时观察记录。在实验开始前，肌条在水浴中平衡至少一小时。水浴为37度的生理盐液(physiological saline solution,PSS)并持续通以95％的氧和5％的二氧化碳。我们以不同频率的电场刺激(1，2，5，10，20，50HZ，3S， 50V)(Grass S48field stimulator,Grass Technologies,RI,USA)用来促使肌条内的神经纤维释放神经递质(模拟体内神经递质的释放)，从而引起肌条的收缩。
实验结果：在不同频率电场的刺激下，膀胱神经纤维主要释放乙酰胆碱和ATP，从而激活膀胱平滑肌的胆碱受体和嘌呤受体引起收缩。如图1所示，膀胱平滑肌在不同频率的电场刺激下引起了显著的收缩力。阿托品可以阻断胆碱力从而留下嘌呤的力。而α，β－meATP可以抑制嘌呤的力，从而留下胆碱的力。如图1所示，NECA，一个非选择性的腺苷受体激动剂能浓度依赖性地抑制膀胱平滑肌嘌呤介导的收缩力，但是只轻度抑制胆碱介导的收缩力。 CGS21680，腺苷A2a受体的选择性激动剂只在μM水平才能一定程度抑制膀胱平滑肌的收缩力，而Bay 60-6583，一个腺苷A2b受体的选择性激动剂，在nM水平就显著抑制膀胱平滑肌的收缩力，并能在10nM水平完全抑制膀胱平滑肌的收缩力，说明腺苷A2b受体主要介导抑制膀胱平滑肌收缩力的作用。
2.腺苷A2b受体基因敲除导致小鼠膀胱功能过度活跃。
实验目的：为确定腺苷A2b受体调节膀胱泌尿功能的作用，我们用腺苷A2b受体基因敲除小鼠模型和尿印迹图进行了评价。
实验方法：把单个12-16周大的小鼠轻轻的放于标准的AN75聚碳酸酯鼠笼内。鼠笼内底表面上放有一张28.5厘米长x 17.5厘米宽的滤纸(Blicks Cosmos Blotting Paper,Cat#: 10422-1005)用以吸收小鼠排出的尿液。在实验的4小时内，小鼠无饮用水但能自由进食。4 小时后收集滤纸。滤纸上小鼠尿液的印迹含有自发荧光的物质，在紫外线(365nm)的照射下 (UVP Chromato-Vue C-75system,UVP,Upland,CA)能够用于摄影成像(相机：EOSRebel T3)。成像图片用ImageJ软件分析定量，并进行统计分析。通过分析已知容量的尿液印迹斑点，我们得到1mm2的尿液等于0.283μl的尿液。
实验结果：如图2所示，小鼠尿液印迹可以在紫外线下清楚的成像用于分析。我们的实验结果显示，与对照组相比，腺苷A2b受体基因敲除小鼠(A2b-/-)4小时内尿液印迹斑点的数量显著增加，同时平均每个斑点的面积显著减少，表明腺苷A2b受体基因敲除小鼠有显著增加的自发排尿的频次，同时平均每次的排尿量显著减少，表明缺失A2b受体的小鼠表现为膀胱过度活跃。
3.Bay 60-6583皮下注射减少排尿次数并增加每次排尿尿容量。
实验目的：为进一步验证腺苷A2b受体对膀胱功能的调节作用，并测试Bay 60-6583对小鼠膀胱功能的调节作用，我们直接在皮下注射Bay 60-6583以观察由此引起的膀胱功能改变以及它可能的治疗作用。
实验方法：利用尿印迹图把单个12‐16周大的小鼠轻轻的放于标准的AN75聚碳酸酯鼠笼内。鼠笼内底表面上放有一张28.5厘米长x 17.5厘米宽的滤纸(Blicks CosmosBlotting Paper,Cat #:10422-1005)用以吸收小鼠排出的尿液。在实验的4小时内，小鼠无饮用水但能自由进食。4 小时后收集滤纸。滤纸上小鼠尿液的印迹含有自发荧光的物质，在紫外线(365nm)的照射下 (UVP Chromato-Vue C-75system,UVP,Upland,CA)能够用于摄影成像(相机：EOS Rebel T3)。成像图片用ImageJ软件分析定量，并进行统计分析。通过分析已知容量的尿液印迹斑点，我们得到1mm2的尿液等于0.283μl的尿液。在实验组中，小鼠在实验前被皮下注射0.2-2mg/kg 的Bay 60‐6583，在对照组中，小鼠被皮下注射同等容量的溶剂。
实验结果：如图3所示，随着注射Bay 60-6583浓度的增加，小鼠排尿频次显著下降，每次排尿容量显著增加，证实了我们的对腺苷A2b受体对膀胱功能的调节作用的研究，证明 Bay 60‐6583为一有效的用于治疗泌尿功能障碍的药物。

Claims (10)

1.腺苷受体激动剂在制备治疗膀胱泌尿功能障碍的药物中的应用,其中所述腺苷受体激动剂是式(I)的化合物：
其中：R1＝heteroaryl,or
R2＝OR’(R’＝H,hydroxyalkyl,cycloalkyl or CH3),or NHCOCH3。
2.根据权利要求1所述的应用，其特征在于：所述膀胱为哺乳动物膀胱。
3.根据权利要求2所述的应用，其特征在于：所述哺乳动物为人、鼠、猪、猫或狗。
4.根据权利要求1所述的应用，其特征在于：所述腺苷受体为其亚单位A2b。
5.根据权利要求1所述的应用，其特征在于：所述膀胱泌尿功能障碍包括尿频，尿急，夜尿，尿痛，膀胱过度活跃综合症，尿失禁，间质性膀胱炎，药物性膀胱炎。
6.根据权利要求1所述的应用，其特征在于：所述腺苷受体激动剂是Bay 60-6583：
7.一种评价腺苷受体激动剂调节哺乳动物膀胱泌尿功能障碍的方法，该方法包括：
利用体外离体的平滑肌确定腺苷受体激动剂对哺乳动物膀胱平滑肌收缩力的调节作用；
敲除哺乳动物腺苷受体基因，以观察由此引起的哺乳动物膀胱功能改变；
给正常哺乳动物直接皮下注射腺苷受体激动剂以观察它在在体条件下对膀胱功能的调节作用，
其特征在于：所述腺苷受体激动剂是式(II)的化合物：
8.根据权利要求7所述的方法，其特征在于：所述腺苷受体为其亚单位A2b基因。
9.根据权利要求7所述的方法，其特征在于：所述哺乳动物为人、鼠、猪、猫或狗。
10.治疗膀胱泌尿功能障碍的药物，其特征在于：所述药物包括腺苷受体激动剂。
CN201711093188.9A 2017-11-08 2017-11-08 腺苷受体激动剂的应用及评价方法及治疗膀胱泌尿功能障碍的药物 Pending CN109745317A (zh)

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