Botros S, Lipkowski A W, Larson D L, Stark P A, Takemori A E, Portoghese P S
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
J Med Chem. 1989 Sep;32(9):2068-71. doi: 10.1021/jm00129a009.
A series of beta-naltrexamine and beta-oxymorphamine derivatives that contain ionizable moieties coupled to the 6 beta-amino group were synthesized in an effort to develop antagonists and agonists that have negligible access into the central nervous system (CNS). Among the beta-naltrexamine derivatives 1-7, all displayed partial agonism on the guinea pig ileal longitudinal muscle preparation except for aspartyl derivative 6, which was a full agonist with activity in the range of morphine. The beta-oxymorphamine derivatives 8-12 were all full agonists with potencies ranging from 1.5 to 6.1 times that of morphine. Among the compounds evaluated in mice for antinociceptive or opioid antagonist activities, aspartyl derivative 6 possessed the greatest difference between peripheral (po or iv) and icv equiactive antagonist doses. Compared to naltrexone, 6 was greater than 100 times more potent by the icv route, but 6000-10,000 times less potent when administered po or icv. The present study suggests that zwitterionic groups are highly effective in preventing penetration of ligands into the CNS. Such ligands may be useful pharmacologic tools for investigation of peripheral opioid mechanisms. Moreover, they could find clinical applications when the central actions are unwanted.
合成了一系列含有与6β-氨基偶联的可离子化部分的β-纳曲胺和β-羟吗啡酮衍生物，旨在开发进入中枢神经系统（CNS）的可能性可忽略不计的拮抗剂和激动剂。在β-纳曲胺衍生物1-7中，除天冬氨酰衍生物6外，其余在豚鼠回肠纵肌制备中均表现出部分激动作用，天冬氨酰衍生物6是一种完全激动剂，活性与吗啡相当。β-羟吗啡酮衍生物8-12均为完全激动剂，效力为吗啡的1.5至6.1倍。在小鼠中评估抗伤害感受或阿片样物质拮抗剂活性的化合物中，天冬氨酰衍生物6在外周（口服或静脉注射）和脑室内等效活性拮抗剂剂量之间的差异最大。与纳曲酮相比，6通过脑室内途径的效力比纳曲酮强100倍以上，但口服或脑室内给药时效力比纳曲酮低6000至10000倍。本研究表明两性离子基团在防止配体进入中枢神经系统方面非常有效。这类配体可能是研究外周阿片样物质机制的有用药理学工具。此外，当不需要中枢作用时，它们可能会有临床应用。
