Bagley J R, Thomas S A, Rudo F G, Spencer H K, Doorley B M, Ossipov M H, Jerussi T P, Benvenga M J, Spaulding T
Chemistry Department, Anaquest, Inc., A BOC Health Care Company, Murray Hill, New Jersey 07974.
J Med Chem. 1991 Feb;34(2):827-41. doi: 10.1021/jm00106a051.
A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.
已经合成了一系列新的1-（杂环烷基）-4-（丙酰苯胺基）-4-哌啶基甲酯和亚甲基甲醚，并进行了药理评估。在小鼠热板试验中，大多数化合物表现出优于吗啡的镇痛作用（半数有效量小于1mg/kg）。这些研究表明，与原型甲酯（卡芬太尼，2）和亚甲基甲醚（舒芬太尼，3和阿芬太尼，4）的4-丙酰苯胺基镇痛药的相应芳基乙基组分相比，许多结构上更多样化且体积更大的芳环系统在药理上具有适应性。化合物9A（1-[2-（1H-吡唑-1-基）-乙基]-4-[(1-氧代丙基）苯基氨基]-4-哌啶甲酸甲酯）表现出可观的μ-阿片受体亲和力，是一种比阿芬太尼更有效且作用时间短的镇痛药，在大鼠中呼吸抑制作用较小。另一方面，对与伤害性传递介导相关的阿片受体（即μ、κ和δ亚型）亲和力可忽略不计的邻苯二甲酰亚胺57A和57B在所有抗伤害感受试验中均显示出镇痛效果。此外，在大鼠转棒试验中，与临床阿片类药物相比，57B在从全麻醉剂量恢复翻正反射后运动协调性恢复更好，而在异氟烷麻醉的大鼠中，57A在超镇痛剂量下心血管功能抑制明显较小。
