类阿片
不
药理学
吗啡
化学
部分激动剂
兴奋剂
阿片受体
芬太尼
不利影响
效力
纳曲酮
受体
医学
体外
生物化学
作者
Maree T. Smith,Dehui Kong,Andy Kuo,Mohammad Zafar Imam,Craig M. Williams
标识
DOI:10.1021/acs.jmedchem.2c01695
摘要
The global “opioid crisis” has placed enormous pressure on the opioid ligand discovery community to produce novel opioid analgesics with superior opioid-related adverse-effect profiles compared with morphine. In this Perspective, the multitargeted opioid ligand strategy for the discovery of opioid analgesics with superior preclinical therapeutic indices relative to morphine is reviewed and discussed. Dual-targeted μ-opioid (MOP)/δ-opioid (DOP) ligands in which the in vitro DOP antagonist potency at least equals that of the MOP agonist activity, and are devoid of DOP or κ-opioid (KOP) agonist activity, are sufficiently promising candidates to warrant further investigation. Dual-targeted MOP/NOP partial agonists have superior preclinical therapeutic indices to morphine and/or fentanyl in nonhuman primates and are also considered promising. Based on the poor preclinical and clinical therapeutic indices of cebranopadol, which is a full agonist at MOP, DOP, and NOP receptors and a partial agonist at the KOP receptor, this pharmacologic template should be avoided.
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