DELIVERY OF OPIOID PEPTIDE ANALOGS TO THE BRAIN

将阿片肽类似物输送至大脑

基本信息

批准号：
2443484
负责人：
NICHOLAS S BODOR
金额：
$ 14.91万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-07-01 至 1999-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2443484
关键词：
analgesia blood brain barrier chemical group chemical structure function drug delivery systems drug design /synthesis /production endogenous opioid enkephalins hydropathy laboratory rat opioid receptor peptide hormone analog pharmacokinetics protective chemical group proteolysis receptor binding tissue /cell culture

项目摘要

The objective of this proposal is to design, synthesize, and characterize the analgesic potential of chemical delivery systems (CDS's) that provide for brain-directed delivery of opioid peptides. Such compounds could significantly improve pain control in critically ill patients, offer more effective treatment for drug addiction and might also be developed for treating several disorders of the central nervous system (CNS) that involve opioid neuropetides. Studies in this proposal use the concept of "molecular packaging" which was conceived in order to circumvent athe primary obstacles that neuroactive peptides encounter int the circulation before reaching CNS target sites. The hydrophilic peptides must penetrate the blood-brain barrier (BBB) and escape peptidase digestion by numerous brain endothelial enzymes. Molecular packaging disguises neuropeptides with three functional groups (T, L, and S) to deliver intact peptide to brain tissue. In the most important step, an enzymatic reactions "locks- in" the CDS by quaternization of a redox targetor, T. The bulky, non- toxic, lipophilic L group masks the peptide structure from peptidases while allowing passive transport through brain endothelial cells. Addition of spacer, S, functions modifies the cleavage rate of free peptide from the molecular package to optimize delivery of opioid peptides at CNS target sites. Preliminary studies demonstrated that molecular packaging can improve CNS delivery of neuropeptides. Manipulation of the S function increased the magnitude of the anticataleptic activity measured after systemic administration of CDS's for a tripeptide analog of thyrotropin releasing hormone *TRH). Feasibility studies indicated that the predicted retrometabolic conversions of an encephalon-CDS's can be monitored. A more important result was the improved analgesic activity shown for the packaged encephalon analog. Specific studies in this proposal optimize the delivery concept for opioid peptides and include systematic examination of each functional group. Physical-chemical and metabolic profiles are examined in vitro to confirm property changes predicted on the basis of drug design. Receptor binding and distribution studies examine drug and key metabolite properties. Analgesic activity is evaluated in selected compounds. The pharmacological profile and initial safety profile of the most promising compounds will be examined for therapeutic potential.

该建议的目的是设计，合成和特征化学输送系统（CDS）的镇痛潜力用于大脑指导的阿片类肽。这样的化合物可以显着改善重症患者的疼痛控制，提供更多有效的药物成瘾治疗治疗涉及的中枢神经系统（CNS）的几种疾病阿片类神经酯。该提案中的研究使用为了绕开融合而被构想的“分子包装” 神经活性肽会遇到循环的主要障碍在到达CNS目标站点之前。亲水性肽必须穿透血脑屏障（BBB）和逃脱肽酶消化脑内皮酶。分子包装掩盖了神经肽与三个功能组（T，L和S）一起将完整的肽传递到脑组织。在最重要的步骤中，酶促反应“锁” 在“通过氧化还原靶向器的Quathizator的CD中，T。有毒的亲脂性L组掩盖了肽酶的肽结构，而允许通过脑内皮细胞被动转运。加法 SPACER，S，功能修改了自由肽的切割速率分子包装以优化中枢神经系统目标的阿片类肽的递送站点。初步研究表明分子包装可以改善神经肽的中枢神经系统递送。操纵S功能增加了在用于甲状腺蛋白的三肽类似物的CDS的全身性给药释放激素 *TRH）。可行性研究表明该预测可以监视脑CD的后代代谢转换。更多重要的结果是包装的改进的镇痛活性脑类似物。该建议中的特定研究优化交付阿片类肽的概念，包括对每种肽的系统检查功能组。在物理化学和代谢概况中检查基于药物设计预测的财产变化的体外。受体结合和分布研究检查药物和关键代谢产物特性。在选定的化合物中评估镇痛活性。这最有前途的药理特征和初始安全性将检查化合物的治疗潜力。