Abbruscato T J, Williams S A, Misicka A, Lipkowski A W, Hruby V J, Davis T P
Department of Pharmacology, University of Arizona, College of Medicine, Tucson, USA.
J Pharmacol Exp Ther. 1996 Mar;276(3):1049-57.
Biphalin (Tyr-D-Ala-Gly-Phe-NH)2 is a unique opioid peptide analog that contains two active enkephalin pharmacophores and is more potent than morphine and etorphine in eliciting analgesia after intrathecal administration. After systemic administration, only a small amount was detected in the brain, but analgesia was observed. Because halogenation of enkephalin analogs has been shown to increase the brain uptake after systemic administration, our research group synthesized both p-[Cl-Phe4,4']biphalin and p-[F-Phe4,4']biphalin. The aim of the present study was to characterize and compare the blood-to-central nervous system (CNS) pharmacokinetics and biological stability of biphalin and related halogenated analogs. The initial screening used an in vitro blood-brain barrier model and identified p-[Cl-Phe4,4')biphalin as the enkephalin analog with the best potential for greater CNS entry. The CNS uptake and stability of biphalin and p-[Cl-Phe4,4']biphalin was examined further using an in situ brain perfusion technique coupled to high-performance liquid chromatography analysis. Both biphalin and its chlorohalogenated analog, were found to significantly enter the CNS through both the blood-brain and blood-cerebrospinal fluid barriers. Chlorohalogenation of biphalin was shown to both improve CNS entry, most likely through an enhancement in lipophilicity, and increase biological stability. This study suggests that incorporation of chlorohalogens at the p-Phe4,4' position is a promising structural modification in the development of biphalin as a successful opioid drug for the clinic.
双啡肽（Tyr-D-Ala-Gly-Phe-NH）₂是一种独特的阿片肽类似物，它含有两个活性脑啡肽药效基团，鞘内给药后在引发镇痛方面比吗啡和埃托啡更有效。全身给药后，在大脑中仅检测到少量药物，但观察到了镇痛效果。由于已证明脑啡肽类似物的卤化可增加全身给药后的脑摄取，我们的研究小组合成了对-[Cl-Phe⁴,⁴']双啡肽和对-[F-Phe⁴,⁴']双啡肽。本研究的目的是表征和比较双啡肽及相关卤化类似物的血脑屏障药代动力学和生物稳定性。初步筛选使用体外血脑屏障模型，确定对-[Cl-Phe⁴,⁴']双啡肽是具有最佳进入中枢神经系统潜力的脑啡肽类似物。使用原位脑灌注技术结合高效液相色谱分析进一步研究了双啡肽和对-[Cl-Phe⁴,⁴']双啡肽的中枢神经系统摄取和稳定性。发现双啡肽及其氯卤化类似物均通过血脑屏障和血脑脊液屏障显著进入中枢神经系统。双啡肽的氯卤化显示出既能改善中枢神经系统的进入，很可能是通过增强亲脂性，又能提高生物稳定性。这项研究表明在对-Phe⁴,⁴'位置引入氯卤是双啡肽作为一种成功的临床阿片类药物开发中一种有前景的结构修饰。
