Zimmerman D M, Cantrell B E, Swartzendruber J K, Jones N D, Mendelsohn L G, Leander J D, Nickander R C
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.
J Med Chem. 1988 Mar;31(3):555-60. doi: 10.1021/jm00398a011.
A representative series of N-substituted derivatives of the morphine-based trans-4a-aryldecahydroisoquinoline were synthesized and evaluated for opioid analgesic activities. Compounds with potent analgesic activity and high affinities for the mu and kappa opioid receptors were discovered. The effect of varying the N-substituent in the trans-4a-aryldecahydroisoquinoline paralleled, to a certain extent, previous findings with other morphine part structures. Replacement of the N-methyl with a phenethyl group significantly increased analgesic potency. The N-cyclopropylmethyl analogue was found in rodents to have mixed agonist-antagonist properties; however, its antagonist activity was far weaker than those reported for the N-(cyclopropylmethyl)morphinan and -benzomorphan derivatives. Resolution of the stereoisomers and determination of their absolute configuration by X-ray crystallography showed that the opioid receptor effects were predominantly found with the 4aR,8aR isomer, the same relative absolute configuration of morphine. Unexpectedly, the 4aR,8aR N-cyclopropylmethyl analogue (compound 30), which in rodents had mixed agonist-antagonist properties similar to those of pentazocine, was found in rhesus monkeys to behave as a full morphine-like agonist.
合成了一系列具有代表性的基于吗啡的反式-4a-芳基十氢异喹啉的N-取代衍生物，并对其阿片样物质镇痛活性进行了评估。发现了对μ和κ阿片受体具有强效镇痛活性和高亲和力的化合物。在反式-4a-芳基十氢异喹啉中改变N-取代基的效果在一定程度上与之前对其他吗啡部分结构的研究结果相似。用苯乙基取代N-甲基显著提高了镇痛效力。在啮齿动物中发现N-环丙基甲基类似物具有混合激动剂-拮抗剂特性；然而，其拮抗剂活性远低于报道的N-(环丙基甲基)吗啉和-苯并吗啡衍生物。通过X射线晶体学拆分立体异构体并确定其绝对构型表明，阿片受体效应主要存在于4aR,8aR异构体中，与吗啡具有相同的相对绝对构型。出乎意料的是，在恒河猴中发现，4aR,8aR N-环丙基甲基类似物（化合物30）表现为完全的吗啡样激动剂，而在啮齿动物中它具有与喷他佐辛类似的混合激动剂-拮抗剂特性。
