拟肽
部分
κ-阿片受体
化学
兴奋剂
立体化学
受体
μ-阿片受体
类阿片
结构-活动关系
阿片受体
肽
生物化学
体外
作者
Aubrie A. Harland,Irina D. Pogozheva,Nicholas W. Griggs,Tyler J. Trask,John R. Traynor,Henry I. Mosberg
标识
DOI:10.1021/acschemneuro.7b00284
摘要
In an effort to expand the structure–activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m-positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p-position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR). The results from a substituted 2-methylindanyl series aligned with the findings from the substituted benzyl series. Our studies culminated in the development of 8c, a mixed-efficacy MOR agonist/KOR agonist with subnanomolar binding affinity for both MOR and KOR.
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