具有口服镇痛活性的阿片/神经肽FF受体多靶点环肽分子的设计和合成及其药理学鉴定

传统阿片类镇痛药已广泛用于中、重度疼痛的治疗，但其临床应用仍受耐受和成瘾等副作用的限制，发展高效、低副作用的镇痛类创新药物是亟待解决的重大科学问题。近年来阿片类多靶点药物备受关注，最新发现的阿片/孤啡肽受体的多靶点分子在恒河猴上可介导无耐受、低成瘾的镇痛作用，为低副作用的阿片类镇痛新药研发提供了全新的思路和策略。本课题组已发现的阿片/神经肽FF（NPFF）受体多靶点分子可产生高效、无耐受镇痛活性。在前期工作基础上，本项目将基于构效关系研究，对已发现的多靶点分子进行三类不同成键方式的环化修饰，在保持其高效、低副作用基础上，以期获得具有口服活性的、长效镇痛的阿片/NPFF受体的多靶点环肽。同时，评价优选环肽分子在各种病理痛中的药理学特性，从分子、细胞和整体动物等水平探讨其无耐受镇痛作用的机制，初步评价其阿片样副作用和成药性。本项目将有助于发展多靶点肽类分子的设计理论，并推动镇痛新药的研发。

The classical opioid analgesics are the mainstay for treatment of moderate and severe pain, however, severe side effects including tolerance and addiction that hamper their clinical use. Currently, the development of novel drugs with powerful antinociception and fewer side effects is an urgent and major scientific concern. In recent years, the development of multi-target opioid drugs has emerged as an attractive therapeutic strategy for pain management. In fact, the multi-target agonists at mu-opioid and nociceptin/orphanin FQ receptors could produce potent, nontolerance-forming analgesia in rhesus monkeys, which is gaining increasing recognition as an effective strategy for the develoment of novel opioid analgesics with limited side-effects. Our group recently developed multi-target peptides that can activate the opioid and NPFF receptors, and produce potent, nontolerance-forming antinociception. On the basis of the previous studies of the multi-target agonists of opioid and NPFF receptors, in the present project, cyclic analogues containing three different types of chemical linkages of the multi-target peptides of opioid and NPFF receptors will be designed and synthesized according to their structure-activities relationship studies. The multi-target cyclic peptides will possess potential druggabilities and oral bioavailability, and also produce powerful antinociception with reduced side-effects. Furthermore, the pharmacological properties and their related mechanisms of these candidate cyclic peptides will be systemically investigated in different pathological pain models. Finally, the opioid-like side effects and druggabilities of these candidate cyclic peptides will also be evaluated. These studies are expected in future to develop the chemical building and modification strategy for multi-target peptides. And it might be helpful to discover candidate drugs for novel analgesics.