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.

7. Project Narrative 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.