REDOX SYSTEMS FOR DELIVERY OF DRUGS TO THE BRAIN

用于将药物输送至大脑的氧化还原系统

基本信息

批准号：
3274591
负责人：
NICHOLAS S BODOR
金额：
$ 17.06万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-02-01 至 1989-06-30
项目状态：
已结题

项目摘要

The proposed project is aimed at developing a general method for specific and/or enhanced delivery to the brain of a variety of biologically active agents, endogenous bioactive compounds and drugs, and to achieve sustained brain-specific delivery of these agents by affecting their bidirectional movement in and out of the brain, using dihydropyridine pyridinium salt-type redox carrier systems. Based on the direct (analytical) and pharmacological evidence for the brain-specific delivery of dopamine coupled to a redox CDS (chemical delivery sstem), it is proposed to investigate CNS delivery of other important neurotransmitters, like GABA and serotonin (via the precursors like tryptophan and 5-OH-tryptophan). The effect of these will also be investigated on the brain concentrations of other CNS amines, neurotransmitters and their metabolites. HPLC and GC-MS will be employed. Detailed studies of the influx of the lipid-soluble form and efflux of the charged species, including the carrier moieties formed after cleavage of the quaternary pyridinium carrier-drug linkage, will be undertaken. The structural requirements for optimum delivery and limitations of the bidirectional movement will be established. Ne redox-type carrier systems are proposed to be investigated to allow more facile brain release of some of the amine containing bioactive compounds. Based on a very prolonged (24 days) activity of brain-specific estradiol-redox carrier CDS, detailed pharmacodynamic approaches are proposed to evaluate the brain-specific delivery of gonadal steroids attached to redox CDS's. Two different directions for the delivery of neuropeptides and related compounds are proposed. One is using the general redox CDS approach. Varios carriers will be employed. The new trigonle-glycine combined carrier has special importance, as it requires peptide link cleavage. The second main direction involves design and evaluation of novel brain-specific peptide analogs based on some recently designed new amino acids. Among the therapeutic drug classes, it is proposed to focus on anticonvulsants and antitumor agents. The proposed approaches include design and testing for delivery of currently used agents and new analogs, which have the intrinsic brain-specific properties. In vitro studies of all of the redox systems will precede their in vivo evaluation: distribution into various organs, metabolism and release kinetics. Pharmacological evaluation of the best systems will be undertaken. Theoretical studies of the energetic and electronic processes will be continued.

拟议的项目旨在为特定的特定方法开发一般方法和/或增强向各种生物活性的大脑的递送剂，内源性生物活性化合物和药物，并实现持续这些药物的双向交付使用二氢吡啶吡啶丁吡丁，进出大脑盐型氧化还原载体系统。基于直接（分析）和大脑特异性多巴胺递送的药理证据耦合到氧化还原CD（化学输送系统），提议研究其他重要神经递质的中枢神经系统传递，例如GABA 和5-羟色胺（通过色氨酸和5-OH-色氨酸的前体）。这些影响还将研究对大脑浓度在其他中枢神经系统胺，神经递质及其代谢产物中。 HPLC和 GC-MS将被雇用。关于涌入的详细研究带电物种的脂溶性形式和外排，包括载体五吡啶载体 - 载体裂解后形成的部分形成将进行联系。最佳的结构要求双向运动的交付和局限性将是已确立的。提议研究NE氧化还原型载体系统为了使一些含有某些胺的大脑更容易释放生物活性化合物。基于非常长的（24天）的活动脑特异性雌二醇 - 雷克斯载体CD，详细的药效学提出了方法来评估性腺的大脑特异性输送氧化还原CD的类固醇。两个不同的方向提出了神经肽和相关化合物的递送。一个正在使用一般的氧化还原CD方法。将雇用Varios载体。新的 Trigonle-Glycine组合载体具有特殊的重要性，因为它需要肽链接裂解。第二个主要方向涉及设计和基于一些新型脑特异性肽类似物的评估设计了新的氨基酸。在治疗药物类别中，是建议专注于抗惊厥药和抗肿瘤剂。提议方法包括设计和测试以交付当前使用的代理和新的类似物，它们具有内在的大脑特异性特性。在所有氧化还原系统的体外研究将在其体内之前评估：分布到各种器官，代谢和释放动力学。最佳系统的药理评估将是进行。能量和电子过程的理论研究将继续。