β-氟芬太尼是对pH敏感的μ阿片受体激动剂。
β-Fluorofentanyls Are pH-Sensitive Mu Opioid Receptor Agonists.
作者信息
Rosas Ricardo, Huang Xi-Ping, Roth Bryan L, Dockendorff Chris
机构信息
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States.
National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, School of Medicine, University of North Carolina Chapel Hill, Chapel Hill, North Carolina 27599-7365, United States.
出版信息
ACS Med Chem Lett. 2019 Aug 13;10(9):1353-1356. doi: 10.1021/acsmedchemlett.9b00335. eCollection 2019 Sep 12.
The concept recently postulated by Stein and co-workers ( , , 966) that mu opioid receptor (MOR) agonists possessing amines with attenuated basicity show pH-dependent activity and can selectively act at damaged, low pH tissues has been additionally supported by in vitro studies reported here. We synthesized and tested analogs of fentanyl possessing one or two fluorine atoms at the beta position of the phenethylamine side chain, with additional fluorines optionally added to the benzene ring of the side chain. These compounds were synthesized in 1 to 3 steps from commercial building blocks. The novel bis-fluorinated analog RR-49 showed superior pH sensitivity, with full efficacy relative to DAMGO, but with 19-fold higher potency (IC) in a MOR cAMP assay at pH 6.5 versus 7.4. Such compounds hold significant promise as analgesics for inflammatory pain with reduced abuse potential.
斯坦因及其同事最近提出的概念（，，966），即具有碱度减弱胺的μ阿片受体（MOR）激动剂表现出pH依赖性活性，并且可以选择性地作用于受损的低pH组织，在此报道的体外研究中得到了进一步支持。我们合成并测试了在苯乙胺侧链的β位具有一个或两个氟原子的芬太尼类似物，并可选择在侧链的苯环上额外添加氟原子。这些化合物由市售原料通过1至3步合成。新型双氟化类似物RR-49表现出优异的pH敏感性，相对于DAMGO具有完全效力，但在pH 6.5与7.4的MOR cAMP测定中，其效力（IC）高19倍。这类化合物作为具有降低滥用潜力的炎性疼痛镇痛药具有重大前景。
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