DELIVERY OF TRH ANALOGS TO THE BRAIN AND CSF

将 TRH 类似物输送至大脑和脑脊液

• 批准号: 3417537
• 负责人: NICHOLAS S BODOR
• 金额: $ 16.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3417537
• 关键词: biological transport; biotransformation; blood brain barrier; brain metabolism; cerebrospinal fluid; chemical structure function; drug delivery systems; drug design /synthesis /production; high performance liquid chromatography; laboratory rat; learning; lipid solubility; mass spectrometry; neuroprotectants; nonhuman therapy evaluation; peptide hormone analog; thyrotropin releasing hormone

The main objective of the proposal is to design, synthesize and investigate chemical delivery systems (CDS's) based on the concept of molecular packaging that make possible the brain delivery and brain targeting of the neuropeptide TRH or its analogues for potential treatment of the cognitive decline, associated with Alzheimer's disease, and of amyotrophic lateral sclerosis. Neuropeptides cannot reach the brain after systemic administration, as the blood-brain-barrier (BBB) prevents entry of these hydrophilic compounds. In addition to physicochemical features (most peptides are hydrophilic), a highly active enzymatic barrier for peptides exists in the BBB which results in their rapid cleavage-fragmentation of peptides, even if they possess sufficient lipophilicity. The novel concept is to provide the peptide molecule a special architecture that enhances lipid solubility and disguises its peptide nature in order to effectively deliver the entire (intact) peptide segment into the brain. In the most important step, an enzymatic reaction locks-in the brain delivered molecule. A series of enzymatic biotransformations then cleave the protective functions and allow the formation of the biologically active species. Important structural elements are the bulky polycyclic substituents (non-toxic steroid derivatives such as cholesteryl, cortienyl, or other lipophilic alkyl group, e.g., adamantanethyl) susceptible to cleavage from the peptide by esterase and/or lipase enzymes. Secondly, a dihydropyridine - pyridinium salt-type dual targetor allows the compound to remain at a sustained (locked-in) level after brain delivery. An additional element which may also be needed is a "spacer", consisting of one of two amino acid residues, or a carbamate function which is placed between the targetor and the neuropeptide to be delivered. The spacer allows enzymatic cleavage (endopeptidase or esterase) at the desired site resulting in the controlled and sustained release of the biologically active peptide. Preliminary results fully support the feasibility of the proposed approach to deliver pharmacologically significant amount of neuropeptide (including a TRH analog) into the CNS. Design and synthesis, in vitro hydrolytic, oxidation, and peptide cleavage pattern studies will be carried out to evaluate the compounds, and select candidates for in vivo distribution experiments. Brain uptake and biotransformation of CDS's will be investigated by specific analytical techniques (high-performance liquid chromatography, mass spectrometry, and combinations thereof, already used successfully). Pharmacological tests will be performed to assess the hormonal and CNS effects induced by the central delivery of TRH analogues including cholinergic neuron cytoprotection, and memory/learning tests.

该提案的主要目的是设计，合成和 根据 使大脑递送和大脑的分子包装 靶向神经肽TRH或其类似物的电势 治疗与阿尔茨海默氏病有关的认知能力下降， 和肌萎缩性的侧索硬化症。 神经肽无法到达 全身给药后的大脑，作为血脑屏障（BBB） 防止进入这些亲水性化合物。 此外 物理化学特征（大多数肽是亲水性），高度活跃的 BBB中存在肽的酶屏障，这导致其 即使肽具有足够的足够 亲脂性。 新颖的概念是提供肽分子A 增强脂质溶解度并掩盖其的特殊体系结构 肽性质，以有效地传递整个（完整） 肽段进入大脑。 在最重要的一步中，酶促 反应锁定大脑传递的分子。 一系列酶促 然后，生物转化会裂开保护功能，并允许 生物活性物种的形成。 重要的结构 元素是笨重的多环子取代基（无毒类固醇 诸如胆固醇，皮质基或其他亲脂烷基的衍生物 组，例如，阿甘丹乙基）易受裂解的裂解 酯酶和/或脂肪酶。 其次，二氢吡啶 - 吡啶丁胺 盐型双靶子允许该化合物保持持续 （锁定）大脑输送后的水平。 可能的另一个元素 还需要一个“垫片”，由两个氨基酸之一组成 残留物或靶向器之间放置的氨基甲酸酯功能 和要输送的神经肽。 垫片允许酶促 所需位点的切割（内肽酶或酯酶），导致 生物活性肽的控制和持续释放。 初步结果充分支持了提议的可行性 提供药理大量神经肽的方法 （包括一个TRH类似物）进入中枢神经系统。 设计和合成，体外 水解，氧化和肽裂解模式研究将是 进行评估化合物并选择体内的候选物 分布实验。 CD的大脑吸收和生物转化 将通过特定的分析技术进行研究（高性能 液相色谱，质谱法及其组合， 已经成功使用）。 药理测试将进行 评估中央输送引起的激素和中枢神经系统效应 TRH类似物，包括胆碱能神经元细胞保护和 记忆/学习测试。