含芬太尼类小分子结构的阿片/神经肽FF系统多功能杂聚肽的化学构建和镇痛活性研究

Fentanyl and related analgesics are the first-line drugs for the clinical treatment of pain. However, their long-term therapeutic uses are limited by severe side-effects including addiction, tolerance and respiratory depression, which are the major contributors to opioid crisis. We built the opioid peptides and neuropeptide FF pharmacophore-containing multi-functional peptides. These peptides induced potent antinociception with minimal side-effects and therefore the multi-functional strategy is an attractive strategy for reducing the side-effects of fentanyl and related analgesics. In this project, we try to chemically build a series of novel multi-functional heteromeric peptides using a hybrid strategy containing peptide and small-molecule, based on fentanyl analogs and neuropeptide FF pharmacophore. Moreover, the pharmacological activities, side-effects and druggability of these heteromeric peptides are further evaluated. It is expected that these heteromeric peptides will become candidate analgesic drugs with limited side-effects and good druggability. Furthermore, the pharmacological and pharmacokinetic mechanisms in reducing the side-effects by heteromeric peptides are explored. It is anticipated that the heteromeric strategy could provide a theoretical support for analgesic drug development with limited side-effects. In our preliminary tests, the carboxylfentanyl and neuropeptide FF pharmacophore-containing multi-functional heteromeric peptide FENPFF01 was developed. Moreover, FENPFF01 can cross the blood-brain barrier and induced potent nontolerance-forming analgesia without reinforcing strength, physical dependence and constipation. In a word, we hope to provide a novel strategy for solving the opioid crisis and promote the development of novel analgesics.

芬太尼类阿片药物是临床疼痛治疗的一线药物，但其成瘾、耐受和呼吸抑制等副作用是导致“阿片类药物危机”的重要原因，从而限制了其临床应用范围。本课题组构建的阿片/神经肽FF系统的多功能肽类配体可产生高效、低副作用镇痛，该设计策略有望降低芬太尼类药物的副作用。因此，本项目将基于芬太尼类似物和神经肽FF药效团，构建肽-小分子杂合结构的多功能杂聚肽，通过活性筛选、副作用和初步成药性评价，以期发现高效、低副作用的多功能镇痛候选药物。同时，从药理学和药代动力学角度来探讨多功能杂聚肽副作用降低的机制，为低副作用镇痛药物的进一步开发提供理论指导。前期研究表明基于羧基芬太尼和神经肽FF构建的多功能杂聚肽FENPFF01，可产生阿片受体介导的无耐受镇痛作用，并具有血脑屏障通透性，且无运动加强、生理性成瘾和便秘的副作用。本项目将有望为“阿片类药物危机”的解除提供新策略，同时促进原创性镇痛新药的研发。

芬太尼等阿片类镇痛药物临床疗效显著，但其成瘾、耐受和呼吸抑制等阿片样副作用极大地限制了其临床应用范围。而神经肽FF（NPFF）是一种内源性阿片调节肽，能调节阿片镇痛、耐受、躯体依赖性和成瘾性等。本项目验证了本课题组前期基于阿片肽构建的阿片/神经肽FF系统多功能分子设计策略，进一步以阿片小分子配体芬太尼和肽类配体神经肽FF作为化学模板分子，将它们的关键药效团化学偶联，构建了一系列肽-小分子杂合结构的阿片/神经肽FF系统的多功能杂聚肽，通过活性筛选，获得了一些杂聚肽结构的镇痛分子。特别是杂聚肽FENPFF01，其是同时作用于mu阿片、NPFF1和NPFF2受体的多功能激动剂，对急性痛、炎症痛、内脏痛和手术后痛均表现出高效镇痛活性，且无镇痛耐受、呼吸抑制、成瘾、便秘等常见阿片副作用。药理学和药代动力学手段证实，该类杂聚肽分子副作用降低的机制与NPFF2受体的参与有关。构效关系结果表明，保持神经肽FF药效团的激动活性对于降低该类多功能杂聚肽的阿片副作用具有重要意义。综上所述，多功能杂聚肽FENPFF01为高效、低副作用的镇痛新药研发提供了先导化合物。同时，构建肽-小分子杂合结构的阿片/神经肽FF系统的多功能杂聚肽，也为镇痛新药研发提供了新策略。

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