CN111249279A - 孤啡肽受体特异性拮抗剂j-113397在制备治疗心律失常药物中的应用 - Google Patents
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Abstract
本发明属生物医药技术领域，提供了孤啡肽受体特异性拮抗剂J‑113397在制备治疗心律失常药物中的应用。心率失常为急性心肌缺血诱导的室性心律失常。包括室性早搏、室性心动过速及心室颤动。所述心率失常药物为静脉注射药物。所述孤啡肽受体特异性拮抗剂应用于降低缺血区心肌细胞膜β1受体的表达；1×10‑9 mol/L、1×10‑11mol/L药物浓度对心率不产生影响或影响小；对血流动力学的影响小。J‑113397预处理能够显著降低大鼠急性心肌缺血早期心律失常的发生，从而确定了所述孤啡肽受体特异性拮抗剂J‑113397能成为一种潜在的抗心律失常药物。
Description
技术领域
本发明属于生物医药技术领域，具体涉及孤啡受体特异性拮抗剂J-113397在制备治疗心律失常药物中的应用。
背景技术
孤啡肽是一种十七肽的蛋白配体，其氨基酸序列如下：Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser- Ala-Arg-Lys-Leu-Ala-Asn-Gln，孤啡肽主要分布在中枢神经系统中，特别是与痛觉有关系的神经，同时在外周也有很广泛的分布，比如说肝脏，脾脏，卵巢，胸腺，淋巴结，睾丸等，孤啡肽在中心部位可以调节疼痛，焦虑，摄食，运动，学习和记忆。在外周，它影响心血管，胃肠，泌尿生殖器和呼吸功能【1】。孤啡肽受体是一种七次跨膜的G蛋白偶联受体（GPCR）。与阿片类受体具有高度同源性，但是这种受体不会被低浓度的阿片配体结合或激活。孤啡肽受体激活后对阿片受体介导的效应有调节作用，除此之外它还对其他生理功能起到一定的调节作用【2】。
急性心肌缺血后常有严重的心律失常出现，如室早，室速甚至室颤，缺血性心律失常的发生是导致心源性猝死的重要原因。研究表明急性心肌缺血后心律失常的过程中孤啡肽的表达明显增多，内源性孤啡肽通过PKC途径可以增加急性心肌缺血后心律失常的发生率【3】。急性心肌梗死早期交感神经过度激活，内源性孤啡肽可以调节β受体外化导致缺血性心律失常的发生【4】。因此对内源性孤啡肽的作用进行拮抗可以有效的降低急性心肌缺血后心律失常的发生率，对孤啡肽引起的急性心肌缺血后心功能及相关心肌损伤进行调节。
J-113397，1 - [（3R，4R）-1-环辛基甲基-3-羟甲基-4-哌啶基] -3-乙基-1,3-二氢-2H-苯并咪唑-2-酮。20世纪90年代末，Banyu研究人员发现了第一个有效的和选择性的非肽NOP拮抗剂，研究证明J-113397在天然和重组ORL1上充当纯的，竞争性的，有效的和选择性的拮抗剂【5】。
参考文献：
【1】 Mollereau C, Mouledous L. Tissue distribution of the opioid receptor-like(ORL1) receptor. Peptides. 2000 Jul;21(7):907-17. Review. PubMed PMID: 10998524.
【2】Meunier J;Mouledous L;Topham CM.The nociceptin (ORL1) receptor: molecular cloning and functional architecture.[J].PEPTIDES.2000,Vol.21(NO.7)：893-900.
【3】Han Y，Guo Z，Wang LL，et al. Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction-associated ventricular arrhythmias via PKC-dependent mechanism in rats［J］. Br J Pharmacol，2013，170（3）：614-623.
【4】熊畅,韩毅,郭政.内源性孤啡肽通过调节β1肾上腺素能受体对大鼠缺血性心律失常的影响[J].天津医药,2019,47(03):245-249.）
【5】Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, Kato T, Ohta H,and Iwasawa Y (1999) Discovery of the first potent and selective small moleculeopioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one(J-113397).J MedChem 42:5061–5063。
发明内容
本发明提供了孤啡肽受体特异性拮抗剂J-113397在制备治疗心律失常药物中的应用,孤啡肽受体特异性拮抗剂J-113397预处理能够显著降低大鼠急性心肌缺血早期心律失常的发生，从而确定了所述孤啡肽受体特异性拮抗剂J-113397能成为一种潜在的抗心律失常药物。
本发明由如下技术方案实现的：孤啡肽受体特异性拮抗剂J-113397在制备治疗心律失常药物中的应用，所述孤啡肽受体特异性拮抗剂为1 - [（3R，4R）-1-环辛基甲基-3-羟甲基-4-哌啶基] -3-乙基-1,3-二氢-2H-苯并咪唑-2-酮即J-113397。
所述心率失常为急性心肌缺血诱导的室性心律失常。包括室性早搏、室性心动过速及心室颤动。所述心率失常药物为静脉注射药物。
所述孤啡肽受体特异性拮抗剂J-113397应用于降低缺血区心肌细胞膜β1受体的表达；1×10-9 mol/L、1×10-11mol/L药物浓度对心率不产生影响或影响小；对血流动力学的影响小。
目前临床上使用的抗心律失常药物主要分为以下四类：Ⅰ类：钠通道阻滞药；Ⅱ类：β肾上腺素受体阻滞剂；Ⅲ类：延长动作电位时程药；Ⅳ类：钙通道阻滞剂。而进一步研究发现UFP-101的作用类似于Ⅱ类抗心律失常药物即β肾上腺素受体阻滞剂，主要体现在其能够显著降低急性心肌缺血诱导的心肌细胞β1受体外化，产生抑制β1受体过度激活作用。
但是，J-113397对于心率以及血流动力学的影响则与β肾上腺素受体阻滞剂不完全相同。
HRV数据可以看出急性心肌缺血后交感神经过度激活，J-113397可以显著降低其活性，前期研究显示孤啡肽可以通过调节β受体外化调节急性心肌缺血后心律失常的发生，J-113397降低交感神经活性可能与β受体外化有关。急性心肌缺血后炎症因子明显增多，炎症的发生在心律失常的发生过程中起到重要作用，J-113397预处理后炎性因子TNF-α和IL-1β浓度明显降低。心律失常数据显示J-113397可以明显降低缺血后心律失常的发生，该结果与上述炎性因子结果一致。但是J-113397在心功能方面对心率影响较小，有轻微波动但属正常范围。综上所述，J-113397可以明显降低急性心肌缺血后心律失常的发生，该结果可能与交感神经的激活及炎症的发生进行调节有关。
附图说明
图1为AMI及J-113397拮抗内源性N/OFQ15分钟内对LVSP的影响；图2为AMI及J-113397拮抗内源性N/OFQ15分钟内对LVEDP的影响；图3为AMI及J-113397拮抗内源性N/OFQ15分钟内对HR的影响；图4为AMI及J-113397拮抗内源性N/OFQ15分钟内对+dp/dtmax的影响；图5为AMI及J-113397拮抗内源性N/OFQ15分钟内对-dp/dtmax的影响。
具体实施方式
1、材料和方法：实验材料和设备：本发明所采用的化合物J-113397(CAS:217461-40-0)、为商务采购所得；ELISA试剂盒：酶免公司；AlC-V8小动物呼吸机：上海澳尔科特公司；RM6240BD电生理信号记录仪：成都仪器厂；酶标仪：美国赛默飞公司。
2、急性心肌缺血模型的建立以及分组
实验动物：实验动物选用清洁级雄性SD大鼠50只，250-280g，购自山西医科大学实验动物中心，6～8周龄，适应性喂养1周。动物实验经山西医科大学伦理委员会批准。
实验动物分组：采用随机数字表法分为5组（n=10）：（1）假手术组（Sham组）；（2）结扎左冠状动脉前降支（冠脉）组（CAO组）；孤啡肽受体拮抗剂（J-113397）预处理组（J组），J组根据浓度梯度分为三个亚组，即（3）J-Ⅰ组（1×10-7 mol/L）、（4）J-Ⅱ组（1×10-9 mol/L）、（5）J-Ⅲ组（1×10-11 mol/L）。
Sham组仅开胸穿线但不结扎冠脉；CAO组开胸后结扎左冠状动脉前降支；J-Ⅰ组、J-Ⅱ组、J-Ⅲ组在结扎冠脉前10 min经尾静脉按1 mL/kg注射特异性孤啡肽受体拮抗剂J-113397；其余2组给予等容量生理盐水。
建立大鼠急性心肌缺血模型：大鼠称质量后以质量分数为25%的乌拉坦（1.2 g/kg）进行腹腔注射麻醉，将大鼠仰卧位固定于操作台上连接生物信号采集系统记录标准Ⅱ导联心电图，并经右侧颈内静脉置入信号采集导管至左心室。气管切开置入气管导管，连接小动物呼吸机施行机械通气，呼吸机潮气量设为8 mL/kg，呼吸频率70次/min。稳定15 min后，按1 mL/kg经尾静脉分别注入生理盐水、J-113397。10 min后在左侧第四肋间隙开胸，以5-0无损伤缝线的弯针从左心耳右缘进针，肺动脉圆锥左缘出针结扎左冠状动脉前降支。而后可见Ⅱ导联心电图出现ST段逐渐抬高并渐与QRS波融合，心肌前壁组织变苍白色随后出现紫绀，可有心律失常出现，提示造模成功。
3、实验方法：心律失常数据的采集分析以及评分：将各组大鼠冠脉结扎后15min内心律失常进行计数和分析并对心律失常进行评分(参考文献：Han Y，Guo Z，Wang LL，et al. Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction-associated ventricular arrhythmias via PKC-dependent mechanism in rats［J］. Br J Pharmacol，2013，170（3）：614-623.)，具体评分标准如下：0分，冠脉结扎后1 h内共出现＜50个室早（ventricular ectopic beats，VEB），包括单发室早、室早二联律、室早三联律。1分，出现≥50个VEB。2分，出现1~5次室速（ventricular tachycardia，VT）。3分，出现≥6次VT。4分，出现1次室颤（ventricular fibrillation，VF）。5分，出现2~5次VF。
心功能的记录和分析：将体现大鼠心功能的5个指标(left ventricular systolic pressure (LVSP)、 left ventricular end diastolic pressure (LVEDP)、 heart rate (HR)、 LV+dp/dtmax和 LV-dp/dtmax)进行记录，以冠脉结扎15 min内数据进行分析。
统计学方法：应用SPSS23.0软件进行统计分析，正态分布计量资料以均数±标准差（
）表示，多组间比较采用单因素方差分析，组间多重比较采用LSD-t检验，检验水准α=0.05。非正态分布计量资料以M（P 25 ,P 75）表示，采用Kruskal-Wallis H检验，组内两两比较采用Mann-Whitney U检验，并对检验水准α'按Bonferroni法进行校正。
4、结果
J-113397预处理能够显著降低大鼠缺血性心律失常发生，VEB次数明显下降(P < 0.05)、VT+VF发生次数、持续时间及心律失常评分也有下降。见表1。
表1 5组大鼠冠脉闭塞后15min内累计心律失常的比较 （n = 10）
＊＊ P < 0.01；a与Sham组比较，b与CAO组比较，c与J-Ⅰ组比较,d与J-Ⅱ组比较,P < 0.05；A与Sham组比较，B与CAO组比较，P < 0.05。
炎性因子结果：各组大鼠TNF-α浓度比较，与Sham组比较，J-Ⅰ组、J-Ⅱ组、J-Ⅲ组浓度明显升高（P<0.05）；与CAO组比较，J-Ⅰ组、J-Ⅱ组浓度明显下降（P<0.05）；各组大鼠IL-1β浓度比较，与Sham组比较，J-Ⅰ组、J-Ⅱ组、J-Ⅲ组浓度明显升高（P<0.05）；与CAO组比较，J-Ⅰ组浓度明显下降（P<0.05）；。见表2。
表2 5组大鼠CAO后炎性因子浓度比较
**P<0.01,a与Sham组比较，b与CAO组比较，P<0.05；A与Sham组比较，B与CAO组比较，P<0.05。
心率变异度结果：冠脉结扎后15 min内，与Sham组比较，CAO组、J-Ⅰ组、J-Ⅱ组、J-Ⅲ组的SDNN、RMSSD均降低，差异有统计学意义（P<0.05），其中对于SDNN,CAO组与其他各个组间比较差异不具有统计学意义，对于RMSSD，CAO组与J-Ⅱ组比较差异具有统计学意义（P<0.05），各组大鼠LF/HF值比较，与Sham组比较，CAO组、J-Ⅰ组、J-Ⅱ组、J-Ⅲ组的LF/HF均升高，但差异没有统计学意义（P>0.05），与CAO组比较J-Ⅰ组、J-Ⅱ组、J-Ⅲ组的LF/HF降低，差异有统计学意义（P<0.05）。其余两组指标LF和HF,与Sham组比较CAO组、J-Ⅰ组、J-Ⅱ组、J-Ⅲ组的LF均升高，但差异没有统计学意义（P>0.05）。与Sham组比较CAO组、J-Ⅰ组、J-Ⅱ组、J-Ⅲ组的HF均降低，但差异没有统计学意义（P>0.05）。如表3所示。
表3 5组大鼠CAO后15min内心率变异度比较
**P<0.01,a与Sham组比较,P<0.05,b与CAO组比较,P<0.05。
心功能结果：冠脉结扎后15 min内，与CAO组比较，3组拮抗剂组大鼠LVSP均有轻微下降，LVEDP均有轻微上升，但差异无统计学意义；J-Ⅲ组HR有轻微下降，但与其余2组同样差异无统计学意义；其余两组指标（+dp/dtmax,-dp/dtmax）均无明显变化，与CAO组比较差异无统计学意义。如图1-5所示。
HRV数据中LF/HF可以看出急性心肌缺血后交感神经过度激活，使用J-113397可以显著降低其活性。同时急性心肌缺血后炎症因子明显增多，J-113397预处理后炎性因子TNF-α和IL-1β浓度明显降低，其中J-113397（1×10-7mol/l）浓度下炎性因子浓度降低最明显。心律失常数据显示J-113397心律失常次数明显减少，其中降低心律失常发生最适宜浓度是1×10-7mol/l，该结果与上述炎性因子结果一致。图1-5结果显示J-113397对心功能影响较小，最低浓度（1×10-11mol/l）下会导致心动过缓的发生，可能与其溶剂无水乙醇注射入大鼠体内有关。综上所述，J-113397（1×10-7mol/l，1×10-9mol/l，1×10-11mol/l）可以明显降低急性心肌缺血后心律失常的发生。其中1×10-7mol/l，1ml/kg为最佳剂量。
Claims (5)
1.孤啡肽受体特异性拮抗剂J-113397在制备治疗心律失常药物中的应用，其特征在于：所述孤啡肽受体特异性拮抗剂为1 - [（3R，4R）-1-环辛基甲基-3-羟甲基-4-哌啶基] -3-乙基-1,3-二氢-2H-苯并咪唑-2-酮即J-113397。
2.根据权利要求1所述的应用，其特征在于：所述心率失常为急性心肌缺血诱导的室性心律失常。
3.根据权利要求2所述的应用，其特征在于：所述心率失常为室性早搏、室性心动过速及心室颤动。
4.根据权利要求1所述的应用，其特征在于：所述心率失常药物为静脉注射药物。
5.根据权利要求1所述的应用，其特征在于：所述孤啡肽受体特异性拮抗剂J-113397应用于降低缺血区心肌细胞膜β1受体的表达；1×10-9 mol/L、1×10-11mol/L药物浓度对心率不产生影响或影响小；对血流动力学的影响小。
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