具有MOR激动和DOR拮抗特性的双功能EM-2类似物的阿片活性及抗神经性疼痛作用的研究

The opioid analgesics like morphine can easily cause tolerance in clinical analgesia. The higher ratio of DOR:MOR on the cell surface and the activated DOR indicate a greater possibility of developing opioid tolerance. EMs are potent endogenous MOR ligands,so the inquiry of novel peptides based on EMs structure with high efficient and low side effects has become a hotspot in the field of medicine.It would be helpful in the development of suitable μ-opioid agonists therapeutics, but decreased the analgesic tolerance, if the bifunctional EMs ligands with mixed μ-agonist/δ-antagonist activity were designed. Therefore,based on the prophase research, the project is planned to synthesize a series of EM-2 analogs using the proposed methods with several chemical site modifications (Dmt replaced Tyr in positon 1, β-Pro, D-Ala, Sar replaced Pro in position 2, Dmp, Tmp replaced Phe in positon 3), and C-terminal linked by oligo-arg. We expected to improve the opioid affinities, biological stabilities and BBB permeabilities of these analogs, thus enhanced the CNS transportation of the drugs, and then produced potent antinociceptive effects through a central opioid-mediated mechanism. Meanwhile,our purpose is to obtain the bifunctional EM-2 analogs, thereby reducing the drug analgesia tolerance. Evaluting the antinociceptive effects of these EM-2 analogs, and the mechanisms against neuorpathic pain, this project would be of great importance in the development of novel EM-2 derivatives with higher antinociceptive activities, but reduced tolerance and other undesirable side effects. The overall aim of this study is to provide theoretical basis for new clinical analgesics, which possess important clinical scientific values.

吗啡等阿片类镇痛剂在临床止痛中极易引起耐受，细胞膜高比率的DOR:MOR及活化的DOR是形成阿片耐受的原因之一。EMs是MOR内源性的高效配体，探究基于EMs结构的高效、低副作用的新型多肽已成为医药领域的热点。设计具有MOR激动和DOR拮抗活性的双功能EMs配体，对于降低μ-配体的镇痛耐受极具意义。为此，本项目在前期基础上，拟通过多位点修饰（Dmt替换1位Tyr，β-Pro、D-Ala、Sar替换2位Pro，Dmp、Tmp替换3位Phe），以及C-末端连接五聚Arg的方法，合成一系列EM-2类似物。提高类似物的阿片亲和性、生物稳定性和BBB通透性的同时，旨在获得具有μ-激动和δ-拮抗活性的双功能配体，进而降低药物的镇痛耐受。通过对具有医药应用前景的类似物进行抗神经性疼痛活性及镇痛机制的研究，有望为发展EM-2成为有效控制疼痛并减少耐受等副作用的新型镇痛剂提供依据，具有重要的临床科学意义。

阿片及其提取物一直用于镇痛治疗，从阿片中分离出的吗啡就是现在临床应用最广泛的镇痛药物之一。然而吗啡等阿片类镇痛剂在临床止痛中极易引起耐受，细胞膜高比率的DOR:MOR及活化的DOR是形成阿片耐受的原因之一。EMs是MOR内源性的高效配体，探究基于EMs结构的新型、高效、低副作用的多肽衍生物已成为生物医药领域的研究热点。设计具有MOR激动和DOR拮抗活性的双功能EMs配体，对于降低μ-配体的镇痛耐受极具意义。本项目通过多位点修饰（Dmt替换1位Tyr，β-Pro、D-Ala、Sar替换2位Pro，Dmp、Tmp替换3位Phe），以及C-末端连接五聚Arg的方法，设计并合成一系列的新型EM-2类似物。旨在获得具有MOR激动活性和DOR拮抗活性的双功能配体，进而降低药物的镇痛耐受。同时提高类似物的阿片亲和性、生物稳定性和BBB通透性，增强药物向CNS的运输，进而产生中枢介导的高效镇痛活性。本项目主要研究新型EM-2类似物的阿片活性及抗神经性疼痛作用。结果表明，部分新型EM-2类似物具有高效的μ-激动和δ-拮抗的双功能特性，且酶解稳定性显著提高。本研究获得了具有较高BBB通透性和高效镇痛活性的EM-2类似物，其镇痛耐受等阿片样副作用明显降低。部分高效类似物通过与MOR结合后，激活KOR，引起内源性的阿片肽Dyn A的释放，由MOR和KOR共同参与类似物的高效镇痛活性。此外，通过SNI方法建立了稳定的神经病理性疼痛模型，神经降压素系统对部分新型EM-2类似物的无耐受镇痛活性具有明显的调节作用，神经降压素受体2型参与了高效EM-2类似物对神经性疼痛的无耐受镇痛作用。本项目研究有望为发展EM-2成为有效控制疼痛并减少耐受等阿片样副作用的新型镇痛剂及为肽类配体的设计提供理论依据，具有重要的科学价值。