School of Pharmacy , Nanjing Medical University , Nanjing 211166 , China.
School of Biomedical Sciences, Faculty of Medicine , The University of Queensland , Brisbane , QLD 4072 , Australia.
ACS Chem Neurosci. 2019 Jan 16;10(1):201-208. doi: 10.1021/acschemneuro.8b00363. Epub 2018 Sep 14.
A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce β-arrestin2 recruitment. Compound 12 is a potent μ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak β-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak δ-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak β-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.
一系列苯乙基上的苯基被烷基和/或羟基和烷氧基修饰，并且苯胺部分的苯基被苄基或取代的苄基取代的芬太尼类似物被合成。通过评估它们调节福司可林刺激的 cAMP 积累的能力以及诱导β-arrestin2 募集的能力来评估这些化合物的体外阿片受体功能活性。化合物 12 是一种有效的 μ 阿片受体（MOP）受体激动剂，是一种有效的 κ 阿片受体（KOP）受体拮抗剂，具有弱的β-arrestin2 募集活性。化合物 10 和 11 是有效的 MOP 受体激动剂，具有弱的 δ 阿片受体（DOP）受体拮抗剂活性和中等强度的 KOP 受体拮抗剂活性，以及在 MOP 受体上弱的β-arrestin2 募集活性。这些化合物是发现具有相对临床可用的强阿片类镇痛药更少副作用的有效阿片类镇痛药的有前途的先导化合物。
