Controlling Cavitand Conformations for Drug Delivery Studies

控制药物输送研究中的空穴和构象

• 批准号: 7911410
• 负责人: ORION BOYD BERRYMAN
• 金额: $ 4.76万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-16 至 2012-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911410
• 关键词: Acetylcholine; Address; Adverse effects; Affective; Alzheimer' s Disease; Analytical Chemistry; Binding; Brain; Calorimetry; Chemistry; Development; Disease; Drug Controls; Drug Delivery Systems; Educational workshop; Effectiveness; Electrochemistry; Ethics; Grant; International; Journals; Knowledge; Laboratories; Lead; Light; Mass Spectrum Analysis; Molecular; Molecular Biology; Molecular Conformation; Peer Review; Pharmaceutical Preparations; Pharmacotherapy; Publications; Regulation; Research; Research Training; Source; Spectrum Analysis; Stimulus; Structure; System; Therapeutic; Time; Training Programs; Writing; cavitand; controlled release; design; drug distribution; improved; public health relevance; small molecule; symposium; time interval

DESCRIPTION (provided by applicant): The general principle of this proposal is to use external stimuli (light, small molecules and electrochemistry) to release guest molecules bound inside of container molecules (cavitands). The long term objective of this proposal is to develop controlled drug delivery systems. Systems with exact regulation of drug delivery will protect reactive drugs and allow them to be administered at specific time intervals (temporal control) resulting in improved effectiveness of drug therapy. Determining which sources of external stimuli are most affective and understanding the rules that govern the release of bound guest molecules will be paramount to this study. The synthesis and design of three classes of cavitands containing functionality that executes a well-defined structural change in the presence of external stimulus is presented. NMR, UV-Vis spectroscopy, cyclic voltammetry, mass spectrometry and isothermal calorimetry will all be exploited to ascertain the structures and dynamics of these systems. The specific aims of this proposal are as follows: 1) Controlled Molecular Space - design and synthesize three classes of cavitands that are sensitive to external stimuli (light, small molecules and electrochemistry). 2) Altering Form - explore the effects that external stimuli have on cavitand conformations. 3) Controlling Function - determine which forms of external stimuli are suitable to control the release of guest molecules from cavitands. Can external stimulus be used to control the function of cavitand molecules? A strategy is proposed to regulate the catalytic function of a cavitand. The fundamental knowledge required to develop molecules capable of controlled drug release will be gained from this research. The cavitands proposed herein are excellent hosts for important bio-relevant molecules like acetylcholine. The controlled capture and release of these molecules will help us treat diseases such as Alzheimer's that are associated with acetylcholine deficiencies in the brain. The proposed research training program will include laboratory synthesis, analytical chemistry, presentations at national and international conferences (Gordon, ACS and ISMSC), courses in bio-related fields (Bioorganic Chemistry and Molecular Biology) and ethics, grant writing workshops and publication in peer reviewed journals. PUBLIC HEALTH RELEVANCE: The study of what external stimulus is best suited to release bound guest molecules and the mechanism by which it operates will lead to the development of new drug delivery systems. Precise control of guest release will allow us to address the deficiencies of current temporal control of drug delivery (when a drug is delivered over an extended period of time or at specific time intervals during treatment). Exact regulation of drug delivery will result in improved effectiveness of drug therapy by stabilizing reactive (quickly metabolized) drug molecules, increasing therapeutic activity as compared to side effects and reducing the number of drug distributions per treatment.

描述（由申请人提供）：该提案的一般原则是使用外部刺激（光，小分子和电化学）来释放容器分子内部绑定的来宾分子（cavitands）。该提案的长期目标是开发受控的药物输送系统。具有准确调节药物输送的系统将保护反应性药物，并允许以特定时间间隔（时间控制）进行给药，从而提高药物治疗的有效性。确定哪些外部刺激的来源是最有力的，并且了解控制限制客体分子释放的规则将对本研究至关重要。出现了包含三类的cavitands的合成和设计，其中包含功能，在存在外部刺激的情况下执行明确定义的结构变化。 NMR，UV-VIS光谱，环状伏安法，质谱和等温量热法都将被利用以确定这些系统的结构和动力学。该提案的具体目的如下：1）受控的分子空间 - 设计并合成了对外部刺激敏感的三类cavitands（光，小分子和电化学）。 2）改变形式 - 探索外部刺激对腔和构象的影响。 3）控制功能 - 确定哪种形式的外部刺激适合控制从Cavitands释放来宾分子的释放。可以使用外部刺激来控制cavitand分子的功能吗？提出了一种策略来调节Cavitand的催化功能。这项研究将获得开发能够控制药物释放的分子所需的基本知识。本文提出的cavitand是重要的生物相关分子（如乙酰胆碱）的出色宿主。这些分子的受控捕获和释放将有助于我们治疗与大脑中乙酰胆碱缺乏相关的阿尔茨海默氏病等疾病。拟议的研究培训计划将包括实验室合成，分析化学，在国家和国际会议（Gordon，ACS和ISMSC）的演讲，与生物相关领域的课程（生物有机化学和分子生物学）以及伦理学的课程，以及在Peer审查期刊中的授予写作研讨会和出版物。 公共卫生相关性：对最适合释放约束访客分子的外部刺激的研究以及其运作的机制将导致新药输送系统的发展。对访客释放的精确控制将使我们能够解决当前药物输送的时间控制的不足（当在长时间或在治疗过程中以特定时间间隔进行药物时）。与副作用相比，通过稳定反应性（快速代谢）药物分子的反应性（快速代谢）药物分子，通过稳定反应性（快速代谢）药物分子来提高药物治疗的有效性，与副作用相比，增加治疗活性并减少每次治疗的药物分布数量，从而提高了药物治疗的有效性。