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。

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.