在前期多肽研究工作基础上，根据内吗啡肽目前难以成为临床使用的镇痛药物难点及研究现状，以发现镇痛作用强副作用小、同时避免对酶代谢不稳定、难以透过血脑屏障的新型多肽为研究目标，通过采用设计、合成新型的α位可修饰的α-羟基-β-氨基酸及α-氮杂-β-氨基酸替代内吗啡肽序列中的α-氨基酸的策略，保留内吗啡肽的四肽的基本结构, 结合位置扫描法合成骨架可进一步修饰的结构新颖β-拟肽, 经活性及副作用等体内外生物评价，发现具有体内外镇痛活性强、副作用小及代谢稳定性好的β-拟肽苗头化合物，进而在可功能化的苗头拟肽化合物骨架上进行糖基化或酯化修饰，使合成的目标化合物易透过血脑屏障，提高生物利用度，以期发现可专利的新一代镇痛类药物的多肽先导化合物。

This project is based on our preliminary studies regarding the modification of endomorphins in order to make them suitable as analgesic drugs in the clinical. While endomorphins are capable of delivering a potent analgesic response, they have several deleterious properties that make them currently unsuitable for clinical use, such as unwanted side effects, metabolic enzyme instability and limited blood-brain barrier penetration. In order to overcome the unfavorable properties, we will design and synthesis novel α-position modifiable α-hydroxyl-β-amino acids and α-aza-β-amino acids, and then substitute these into the tetrapeptides skeleton of endomorphins and endomorphin analogs. By using a position scanning substitution strategy, the β-peptidomimetics with the most opitimized analgesic activity, side effect profile and metabolic stability will be identified. Further glycosylation and lipidation of the hit β-peptidpmimetics will lead to improved penetration of the blood-brain barrier and bioavailability. The goal of this project is to find novel patentable lead compounds of analgesic drugs.