Roche V F, Roche E B, Lemcke P K, Wire W S, Burks T F
Department of Pharmaceutical Sciences, School of Pharmacy and Allied Health Professions, Creighton University, Omaha, Nebraska 68178.
J Med Chem. 1990 Jan;33(1):245-8. doi: 10.1021/jm00163a040.
Four novel racemic bridged hexahydroaporphine (1 and 2) and isoquinoline (3 and 4) analogues have been synthesized in an attempt to generate bicyclic derivatives of the morphinan ring system. The opioid activity of these analogues has been assessed through membrane-binding studies, in vitro studies in isolated guinea pig ileum and mouse vas deferens, and in vivo studies utilizing the mouse hot plate technique. The bridged isoquinoline precursor molecules were inactive as antinociceptives. Both the racemic phenolic hexahydroaporphine 1 and its 10-methoxy congener 2 demonstrated dose-dependent, albeit weak, antinociceptive activity when administered icv, but they induced lethal convulsions when given subcutaneously. The antinociception elicited by 1 appeared to show very weak opioid character while that caused by 2 was totally nonopioid.
为了合成吗啡喃环系统的双环衍生物，已合成了四种新型外消旋桥连六氢阿朴啡（1和2）和异喹啉（3和4）类似物。这些类似物的阿片样物质活性已通过膜结合研究、在离体豚鼠回肠和小鼠输精管中的体外研究以及利用小鼠热板技术的体内研究进行了评估。桥连异喹啉前体分子作为抗伤害感受剂没有活性。外消旋酚性六氢阿朴啡1及其10-甲氧基同系物2经脑室内给药时均表现出剂量依赖性（尽管较弱）的抗伤害感受活性，但皮下给药时会诱发致命惊厥。1引起的抗伤害感受似乎表现出非常弱的阿片样物质特性，而2引起的抗伤害感受则完全是非阿片样物质的。
