Egleton R D, Mitchell S A, Huber J D, Janders J, Stropova D, Polt R, Yamamura H I, Hruby V J, Davis T P
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave., P.O. Box 245050, Tucson, AZ 85724, USA.
Brain Res. 2000 Oct 20;881(1):37-46. doi: 10.1016/s0006-8993(00)02794-3.
The blood-brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cyclic opioid peptide [D-Cys(2,5),Ser(6),Gly(7)] enkephalin. The peptide was glycosylated on the Ser(6) via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague-Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the delta-opioid receptor, and mixed effect on binding to the mu-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C.
血脑屏障会阻止许多具有潜在治疗作用的肽类药物进入大脑。糖基化已显示出作为一种改善向中枢神经系统递送的方法的潜力。先前的研究表明，糖基化阿片类药物的生物利用度提高，中枢介导的镇痛作用增强。在本研究中，我们研究了糖基化对环阿片肽[D-Cys(2,5),Ser(6),Gly(7)]脑啡肽的影响。该肽通过与各种糖部分和排列的O-连接在Ser(6)上进行糖基化。然后研究这些肽在雌性Sprague-Dawley大鼠中的受体结合、理化特性、原位脑摄取以及在雄性ICR小鼠中的抗伤害感受作用。糖基化导致与δ-阿片受体的亲和力略有下降，对与μ-阿片受体的结合产生混合效应。糖基化导致亲脂性显著降低，与牛血清白蛋白的结合略有减少。原位灌注显示，几种糖基化肽的脑摄取提高了98%，并且这些肽的伤害感受曲线总体上遵循肽进入大脑的顺序，AUC增加了39倍。
