偏向性配体--阿片类镇痛药设计新思路

Biased Ligand——Novel Paradigm for Opioid Analgesics

吗啡等阿片类药物作为镇痛药应用已有数百年历史,但其致呼吸抑制、耐受和成瘾等副作用限制了该类药物的使用,因此人们一直致力于寻找副作用更低的新型镇痛药。近年研究发现,μ阿片受体下游除了经典的G蛋白依赖型通路外,还独立存在由β-arrestin介导的信号通路,吗啡激活μ阿片受体产生的镇痛、镇静效应主要通过G蛋白依赖型通路介导,而胃肠功能紊乱、呼吸抑制、耐受等副反应则由β-arrestin依赖型通路介导。如果能发现只激活G蛋白依赖型通路而不激活β-arrestin依赖型通路的偏向性配体,就可能得到镇痛效应强而副作用低的化合物,这为设计新型强效、低副作用的阿片类镇痛药提供了新思路。该文将对μ阿片受体下游β-arrestin依赖型信号通路及偏向性配体的发现、发展和应用进行综述。

Morphine and related opioids have been used as clinical analgesics for centuries,but various side effects-which include respiratory depression,tolerance and addictionset a limit to medication.Consequently,unremitting efforts have been directed towards the discovery of effective and nonlethal pain killers.Recent studies identified a novelβ-arrestindependent pathway throughμ-opioid receptor and indicated that side effects of morphine are mediated throughβ-arrestin-dependent pathway while G-protein-dependent pathway is thought to confer analgesia,which means biased ligands to G-protein signaling are possible analgesics without side effects.The theory of biased ligands may provide a novel strategy to design better and safer opioid analgesics.In this review,we summarized the discovery,development and application ofβ-arrestin-dependent pathway and biased ligands.