Buolamwini J K, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Drug Des Discov. 1992 Jul;8(4):301-12.
The syntheses and antinociceptive activities of all three isomeric 1-[2-(pyridyl)ethyl]-4-(propionanilido)-piperidine isosteres (11a-c) of fentanyl (1) are described. The 2- (11a), 3- (11b) and 4-pyridyl (11c) isomers exhibited 10, 2 and 0.2 times the antinociceptive activity of fentanyl, respectively. The ED50 values for 11a, 11b, 11c and fentanyl in the rat 4% NaCl-induced writhing test were 0.00023, 0.00085, 0.0087 and 0.0021 mg/kg sc, respectively. The 3-pyridyl (11b) and 4-pyridyl (11c) compounds were further elaborated to the 6-phenyl-1,6-dihydropyridine (12), C-2 H, Me, n-Bu and Ph 1,2-dihydropyridine (13a-d) analogues having a phenoxycarbonyl substituent on the dihydropyridine ring nitrogen. The most active compound in this series was 1-(2-[3-(1-phenoxycarbonyl-6-phenyl-1,6-dihydropyridyl)ethyl ])-4- (propionanilido)piperidine (12), which provided a 58% inhibition of writhing at a dose of 0.4 mg/kg sc. 1-(2-[4-(1-phenoxycarbonyl-1,2-dihydropyridyl)ethyl])-4- (propionanilido)piperidine (13a) exhibited an ED50 of 1.3 mg/kg sc, indicating a decrease in antinociceptive activity of about a 100 fold relative to the parent 4-pyridyl compound (11c). The dihydropyridine analogues 12 and 13 exhibit substantial antinociceptive activity relative to meperidine (ED50 = 0.6 mg/kg sc). The muscular rigidity effect induced by the pyridine compounds (11a-c) at a dose of 4 mg/kg sc, was not illicited by the dihydropyridine analogues at the same dose, or at a high dose of 40 mg/kg sc (13a). Compounds 12 and 13 may therefore be useful lead compounds for the development of more useful 4-anilidopiperidines if the antinociceptive activity can be dissociated from the muscular rigidity effect.
描述了芬太尼（1）的三种异构的1-[2-(吡啶基)乙基]-4-(丙酰苯胺基)哌啶电子等排体（11a - c）的合成及镇痛活性。2 - （11a）、3 - （11b）和4 - 吡啶基（11c）异构体的镇痛活性分别为芬太尼的10倍、2倍和0.2倍。在大鼠4%氯化钠诱导的扭体试验中，11a、11b、11c和芬太尼的半数有效剂量（ED50）分别为0.00023、0.00085、0.0087和0.0021mg/kg皮下注射。3 - 吡啶基（11b）和4 - 吡啶基（11c）化合物进一步衍生为在二氢吡啶环氮上具有苯氧羰基取代基的6 - 苯基 - 1,6 - 二氢吡啶（12）、C - 2 H、Me、n - Bu和Ph 1,2 - 二氢吡啶（13a - d）类似物。该系列中活性最高的化合物是1-(2-[3-(1 - 苯氧羰基 - 6 - 苯基 - 1,6 - 二氢吡啶基)乙基])-4-(丙酰苯胺基)哌啶（12），在0.4mg/kg皮下注射剂量时能产生58%的扭体抑制率。1-(2-[4-(1 - 苯氧羰基 - 1,2 - 二氢吡啶基)乙基])-4-(丙酰苯胺基)哌啶（13a）的ED50为1.3mg/kg皮下注射，表明其镇痛活性相对于母体4 - 吡啶基化合物（11c）降低了约100倍。相对于哌替啶（ED50 = 0.6mg/kg皮下注射），二氢吡啶类似物12和13表现出显著的镇痛活性。吡啶化合物（11a - c）在4mg/kg皮下注射剂量时诱导的肌肉强直效应，在相同剂量或40mg/kg皮下注射高剂量时，二氢吡啶类似物（13a）并未引发。因此，如果镇痛活性能够与肌肉强直效应分离，化合物12和13可能是开发更有用的4 - 苯胺基哌啶类药物的有用先导化合物。
