Bagley J R, Wynn R L, Rudo F G, Doorley B M, Spencer H K, Spaulding T
Chemistry Groups, BOC Technical Center, Murray Hill, New Jersey 07974.
J Med Chem. 1989 Mar;32(3):663-71. doi: 10.1021/jm00123a028.
A research program based on certain heterocyclic modifications (12-50) of the fentanyl (1) molecule has generated a novel class of opioids. In the mouse hot-plate test, these compounds were weaker analgesics than 1. Two types of antagonists were observed in morphine-treated rabbits: those (e.g., 28) that reversed both respiratory depression and analgesia and those (e.g. 32) that selectively reversed respiratory depression. Evaluation of in vitro binding affinities to rat brain opioid receptors was inconclusive for a common locus of action for the agonist as well as the antagonist component. Further pharmacological evaluation of 32, N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide, in the rat showed it to be a potent analgesic (ED50 = 0.07 mg/kg, tail-flick test) with little cardiovascular and respiratory depression when compared to fentanyl.
基于芬太尼（1）分子的某些杂环修饰（12 - 50）开展的一项研究计划产生了一类新型阿片类药物。在小鼠热板试验中，这些化合物作为镇痛药比1弱。在吗啡处理的兔子中观察到两种类型的拮抗剂：一类（如28）能同时逆转呼吸抑制和镇痛作用，另一类（如32）能选择性逆转呼吸抑制。对这些化合物与大鼠脑阿片受体的体外结合亲和力评估未能确定激动剂和拮抗剂成分的共同作用位点。对32，N -（2 - 吡嗪基）- N -（1 - 苯乙基 - 4 - 哌啶基）- 2 - 呋喃甲酰胺在大鼠中的进一步药理学评估表明，与芬太尼相比，它是一种强效镇痛药（ED50 = 0.07 mg/kg，甩尾试验），对心血管和呼吸的抑制作用很小。
