WO2019091434A9 - Applications of and evaluation method for adenosine receptor agonist, and drugs for treating uresis dysfunction of bladder - Google Patents

Applications of and evaluation method for adenosine receptor agonist, and drugs for treating uresis dysfunction of bladder Download PDF

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WO2019091434A9
WO2019091434A9 PCT/CN2018/114638 CN2018114638W WO2019091434A9 WO 2019091434 A9 WO2019091434 A9 WO 2019091434A9 CN 2018114638 W CN2018114638 W CN 2018114638W WO 2019091434 A9 WO2019091434 A9 WO 2019091434A9
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  • OBJECTIVE To test the effect of A2b adenosine receptor agonists such as Bay 60-6583 on contractile force of bladder smooth muscle, we used electromyography to measure the response of isolated muscle strips to Bay 60-6583.

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Abstract

Applications of an adenosine receptor agonist in the preparation of drugs for treating uresis dysfunctions of bladders of mammals, and a method for evaluating the adenosine receptor agonist in regulation of uresis dysfunctions of the bladders of the mammals.

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Application and evaluation method of adenosine receptor agonist and medicine for treating bladder urinary dysfunction 技术领域Technical field
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。The present invention relates to the use of adenosine receptor agonists for the preparation of a medicament for the treatment of bladder urinary dysfunction, and for the evaluation of adenosine receptor agonists for the regulation of bladder urinary dysfunction in mammals.
背景技术Background technique
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。Bladder urinary dysfunction such as frequent urination, urgency, nocturia, dysuria, overactive bladder syndrome, urinary incontinence, interstitial cystitis, drug cystitis (Ketamine cystitis), etc. affect at least 50% > 40-year-old crowd. Current treatment options are limited, including: control of fluid intake, drug control, use of adult diaper, and surgical treatment. As far as drugs are concerned, there are mainly: 1. First-line anticholinergic drugs, but currently oral dosage forms have limited efficacy and side effects (mostly abandoned); 2. Recently, β3 receptor agonists are used for treatment, which have certain curative effects but have large side effects; 3. The FDA recently approved BOTOX for local injection of the bladder to treat bladder overactivity by local paralysis of the bladder nerve endings.
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。Adenosine receptors can be divided into four subunits: A1, A2a, A2b, and A3. It has not been reported about how adenosine receptor signaling and its agonists regulate urinary dysfunction in the body, and as a possible clinical treatment for urinary dysfunction.
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。In addition, there is a big misunderstanding in the current research in the field of urology: mechanically equalizes the activity of the bladder and reduces the contractile force of the smooth muscle of the bladder. In fact, the reduction of contractile force of bladder smooth muscle may reduce the degree of bladder activity, but it may directly lead to urinary retention or urinary incontinence, resulting in a decrease in the frequency of bladder urination and a decrease in capacity. Therefore, the regulation of contractile force of bladder smooth muscle in vitro cannot be directly used to predict its regulation of bladder urinary function. In addition, in the urine storage period, the bladder smooth muscle needs to slowly relax under the condition of maintaining a certain contraction force, so the inhibitory effect of the drug on the contractile force of the bladder smooth muscle in vitro does not necessarily indicate the relaxation of the bladder during the storage phase in the body. Therefore, the regulation of the drug's urinary function must be finally verified by in vivo experiments. Based on these erroneous understandings, the current research on urinary function mechanism and drug evaluation focuses on the level of cells and tissues, but lacks a comprehensive evaluation system. This has seriously impeded the study of regulating the urinary function of the corresponding drugs.
发明内容Summary of the invention
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。In view of the above-mentioned prior art problems, an object of the present invention is to provide an adenosine receptor agonist which can be used in the preparation of a medicament for treating bladder urinary dysfunction.
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。Another object of the present invention is to provide a method for evaluating adenosine receptor agonists for modulating bladder urinary dysfunction in a mammal.
为达到上述目的，本发明采用以下技术方案：In order to achieve the above object, the present invention adopts the following technical solutions:
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：The use of an adenosine receptor agonist for the preparation of a medicament for the treatment of bladder urinary dysfunction, wherein the adenosine receptor agonist is a compound of formula (I):
Figure PCTCN2018114638-appb-000001
Figure PCTCN2018114638-appb-000001
其中：R 1＝heteroaryl,or
Figure PCTCN2018114638-appb-000002
Where: R 1 = heteroroaryl, or
Figure PCTCN2018114638-appb-000002
R 2＝OR’(R’＝H,hydroxyalkyl,cycloalkyl or CH 3),or NHCOCH3。 R 2 =OR'(R'=H, hydroxyalkyl, cycloalkyl or CH 3 ), or NHCOCH3.
优选的，所述膀胱为哺乳动物膀胱。Preferably, the bladder is a mammalian bladder.
优选的，所述哺乳动物为人、鼠、猪、猫或狗。Preferably, the mammal is a human, a mouse, a pig, a cat or a dog.
优选的，所述腺苷受体为其亚单位A2b。Preferably, the adenosine receptor is its subunit 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。Preferably, the bladder urinary dysfunction includes frequent urination, urgency, nocturia, dysuria, overactive bladder syndrome, urinary incontinence, interstitial cystitis, and drug cystitis.
优选的，所述腺苷受体激动剂是Bay 60-6583：Preferably, the adenosine receptor agonist is Bay 60-6583:
Figure PCTCN2018114638-appb-000003
Figure PCTCN2018114638-appb-000003
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：A method for evaluating adenosine receptor agonists for modulating bladder urinary dysfunction in a mammal, the method comprising:
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；The effect of adenosine receptor agonist on the contractile force of mammalian bladder smooth muscle is determined by using isolated muscle in vitro;
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；Knockout the mammalian adenosine receptor gene to observe the resulting changes in bladder function in mammals;
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，Direct injection of adenosine receptor agonists into normal mammals to observe its regulation of bladder function under in vivo conditions,
所述腺苷受体激动剂是式(II)的化合物：The adenosine receptor agonist is a compound of formula (II):
Figure PCTCN2018114638-appb-000004
Figure PCTCN2018114638-appb-000004
优选的，所述腺苷受体为其亚单位A2b基因。Preferably, the adenosine receptor is its subunit A2b gene.
优选的，所述哺乳动物为人、鼠、猪、猫或狗。Preferably, the mammal is a human, a mouse, a pig, a cat or a dog.
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。Preferably, the bladder urinary dysfunction includes frequent urination, urgency, nocturia, dysuria, overactive bladder syndrome, urinary incontinence, interstitial cystitis, and drug cystitis.
本发明的有益效果：The beneficial effects of the invention:
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。The invention adopts the above technical scheme, can effectively increase the bladder capacity and reduce the frequency of urination, and thus can be used as an effective medicine for treating urinary dysfunction.
具体实施方式Detailed ways
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。The invention includes a method of modulating contractile force of bladder smooth muscle, the method comprising injecting an effective amount of an adenosine receptor agonist for a mammal in need thereof, preferably agonist Bay60-6583, said adenosine receptor being sub Unit 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：The invention also relates to a method for evaluating an A2b adenosine receptor agonist for modulating bladder urinary dysfunction in a mammal:
(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；(1) using an in vitro isolated smooth muscle to determine the regulatory effect of an A2b adenosine receptor agonist such as Bay 60-6583 on contractile force of mammalian bladder smooth muscle;
(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。(2) Mouse A2b adenosine receptor gene was knocked out to observe the resulting changes in bladder function in mammals.
(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。(3) Direct injection of an A2b adenosine receptor agonist such as Bay 60-6583 into a normal mammal to observe its regulation of bladder function under body conditions.
以小鼠为实验对象，具体实验过程如下：Taking mice as experimental subjects, the specific experimental process is as follows:
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。1. A2b adenosine receptor agonists such as Bay 60-6583 can selectively inhibit the contractile force of mouse bladder smooth muscle.
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。OBJECTIVE: To test the effect of A2b adenosine receptor agonists such as Bay 60-6583 on contractile force of bladder smooth muscle, we used electromyography to measure the response of isolated muscle strips to Bay 60-6583.
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 S48 field 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。Experimental method: The bladder of male C57BL/6J mice of 12-16 weeks old was used for the experiment. The smooth muscle of the bladder after removal of the inner epidermis was divided into four strips of 5-7 mm long and 2-3 mm wide. One end of the muscle strip is fixed to the shelf by a 6-0 wire, and the other end is connected to the force sensor with a 6-0 wire. The muscle strips were placed between two platinum electrodes on the shelf and placed in an SI-MB4 water bath system (World Precision Instruments, FL, USA). The force signal of the muscle strip is converted into a digital signal by the TBM 4M signal converter and amplified by Powerlab and recorded in real time by the Chart software. The muscle strips were equilibrated in the water bath for at least one hour before the start of the experiment. The water bath is a 37 degree physiological saline solution (PSS) with 95% oxygen and 5% carbon dioxide. We used electric field stimulation at different frequencies (1, 2, 5, 10, 20, 50HZ, 3S, 50V) (Grass S48 field stimulator, Grass Technologies, RI, USA) to promote the release of neurotransmitters from nerve fibers in the muscle strip. (Simulates the release of neurotransmitters in the body), causing contraction of the muscle strips.
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。如表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。Experimental results: Under the stimulation of different frequency electric fields, bladder nerve fibers mainly release acetylcholine and ATP, thereby activating the contraction of choline receptors and purine receptors of bladder smooth muscle. As shown in Table 1, bladder smooth muscle caused significant contractile force under electric field stimulation at different frequencies. Atropine can block choline forces and leave a force. And α,β-meATP can inhibit the force of sputum, leaving the force of choline. As shown in Figure 1, NECA, a non-selective adenosine receptor agonist, inhibited bladder smooth muscle spasm-mediated contractility in a concentration-dependent manner, but only mildly inhibited choline-mediated contractility. CGS21680, a selective agonist of adenosine A2a receptor, only inhibits the contractile force of bladder smooth muscle at a level of μM, whereas Bay 60-6583, a selective agonist of adenosine A2b receptor, significantly inhibits at the nM level. The contractile force of bladder smooth muscle can completely inhibit the contractile force of bladder smooth muscle at 10 nM level, indicating that adenosine A2b receptor mainly mediates the contractile force of bladder smooth muscle.
Figure PCTCN2018114638-appb-000005
Figure PCTCN2018114638-appb-000005
表1Table 1
2.腺苷A2b受体基因敲除导致小鼠膀胱功能过度活跃。2. Adenosine A2b receptor gene knockout leads to overactive bladder function in mice.
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。OBJECTIVE: To determine the role of adenosine A2b receptor in regulating bladder urinary function, we evaluated the adenosine A2b receptor knockout mouse model and the urine blot.
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：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1mm 2的尿液等于0.283μl的尿液。 Experimental method: A single 12-16 week old mouse was gently placed in a standard AN75 polycarbonate squirrel cage. A 28.5 cm long x 17.5 cm wide filter paper (Blicks Cosmos Blotting Paper, Cat#: 10422-1005) was placed on the inner surface of the squirrel cage to absorb urine from the mice. Within 4 hours of the experiment, the mice had no drinking water but were able to eat freely. The filter paper was collected after 4 hours. The imprint of mouse urine on the filter paper contains autofluorescence and can be used for photographic imaging under ultraviolet (365 nm) irradiation (UVP Chromato-Vue C-75 system, UVP, Upland, CA) (camera: EOS Rebel T3). The images were analyzed and quantified using ImageJ software and statistical analysis was performed. By analyzing the urine blot spots of known capacity, we obtained 1 mm 2 of urine equal to 0.283 μl of urine.
实验结果：如表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。Experimental results: As shown in Table 2, mouse urine blots can be clearly imaged for analysis under ultraviolet light. Our results showed that the number of urinary imprinted spots in the adenosine A2b receptor knockout mice (A2b-/-) was significantly increased within 4 hours compared with the control group, and the area of each spot was significantly reduced. It was shown that adenosine A2b receptor knockout mice had a significantly increased frequency of spontaneous urination, while the average daily urinary output was significantly reduced, indicating that mice lacking the A2b receptor showed overactive bladder.
Figure PCTCN2018114638-appb-000006
Figure PCTCN2018114638-appb-000006
表2Table 2
3.Bay 60-6583皮下注射减少排尿次数并增加每次排尿尿容量。3. Bay 60-6583 subcutaneous injection reduces the number of urination and increases the urine output per urination.
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。EXPERIMENTAL OBJECTIVE: To further validate the regulation of adenosine A2b receptor on bladder function and to test the regulation of bladder function in mice by Bay 60-6583, we directly injected Bay 60-6583 to observe the resulting bladder function. Change and its possible therapeutic effects.
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 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：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1mm 2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。 Experimental method: A single 12-16 week old mouse was gently placed in a standard AN75 polycarbonate squirrel cage using a urine blot. A 28.5 cm long x 17.5 cm wide filter paper (Blicks Cosmos Blotting Paper, Cat#: 10422-1005) was placed on the inner surface of the squirrel cage to absorb urine from the mice. Within 4 hours of the experiment, the mice had no drinking water but were able to eat freely. The filter paper was collected after 4 hours. The imprint of mouse urine on the filter paper contains autofluorescence and can be used for photographic imaging under ultraviolet (365 nm) irradiation (UVP Chromato-Vue C-75 system, UVP, Upland, CA) (camera: EOS Rebel T3). The images were analyzed and quantified using ImageJ software and statistical analysis was performed. By analyzing the urine blot spots of known capacity, we obtained 1 mm 2 of urine equal to 0.283 μl of urine. In the experimental group, mice were subcutaneously injected with 0.2-2 mg/kg of Bay 60-6583 before the experiment, and in the control group, mice were subcutaneously injected with an equal volume of solvent.
实验结果：如表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。Experimental results: As shown in Table 3, with the increase of the concentration of Bay 60-6583, the frequency of urination in mice decreased significantly, and the urinary capacity increased significantly each time, which confirmed our regulation of bladder function by adenosine A2b receptor. The study demonstrated that Bay 60‐6583 is an effective drug for the treatment of urinary dysfunction.
Figure PCTCN2018114638-appb-000007
Figure PCTCN2018114638-appb-000007
表3table 3

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：The use of an adenosine receptor agonist for the preparation of a medicament for the treatment of bladder urinary dysfunction, wherein the adenosine receptor agonist is a compound of formula (I):
    Figure PCTCN2018114638-appb-100001
    Figure PCTCN2018114638-appb-100001
    其中：R 1＝heteroaryl,or
    Figure PCTCN2018114638-appb-100002
    Where: R 1 = heteroroaryl, or
    Figure PCTCN2018114638-appb-100002
    R 2＝OR’(R’＝H,hydroxyalkyl,cycloalkyl or CH 3),or NHCOCH3。 R 2 =OR'(R'=H, hydroxyalkyl, cycloalkyl or CH 3 ), 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。The use according to claim 1 wherein the bladder is a mammalian bladder.
  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。The use according to claim 2, characterized in that the mammal is a human, a mouse, a pig, a cat or a dog.
  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。The use according to claim 1, characterized in that the adenosine receptor is its subunit 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。The use according to claim 1, characterized in that said bladder urinary dysfunction comprises frequent urination, urgency, nocturia, dysuria, overactive bladder syndrome, urinary incontinence, interstitial cystitis, drug cystitis .
  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：The use according to claim 1, wherein the adenosine receptor agonist is Bay 60-6583:
    Figure PCTCN2018114638-appb-100003
    Figure PCTCN2018114638-appb-100003
  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：A method for evaluating adenosine receptor agonists for modulating bladder urinary dysfunction in a mammal, the method comprising:
    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；The effect of adenosine receptor agonist on the contractile force of mammalian bladder smooth muscle is determined by using isolated muscle in vitro;
    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；Knockout the mammalian adenosine receptor gene to observe the resulting changes in bladder function in mammals;
    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，Direct injection of adenosine receptor agonists into normal mammals to observe its regulation of bladder function under in vivo conditions,
    其特征在于：所述腺苷受体激动剂是式(II)的化合物：Characterized in that the adenosine receptor agonist is a compound of formula (II):
    Figure PCTCN2018114638-appb-100004
    Figure PCTCN2018114638-appb-100004
  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。The method of claim 7 wherein said adenosine receptor is its subunit A2b gene.
  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。The method of claim 7 wherein said mammal is a human, a mouse, a pig, a cat or a dog.
  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。A medicament for treating urinary dysfunction of the bladder, characterized in that the medicament comprises an adenosine receptor agonist.
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