We propose the synthesis of a variety of ergot and histrionicotoxin alkaloids that have demonstrated activity in muscular, vascular, and central nervous systems, and nicotinic acetylcholine receptors. The general aim of the program is to develop efficient new synthetic technologies that will allow target molecules and their analogs to be produced in sufficient quantities for detailed pharmacological evaluations. The studies will include direct participation in collaborative SAR studies. The specific targets for the proposed period are elymolclavine, VUFB, perhydronicotoxin, and histoionicotoxin 235A. As many of the ergot alkaloids have multiple pharmacological activities, our aim is to develop methods for efficient syntheses of these compounds and their analogs, this will allow for further structure activity studies and development of these compounds with more selective activities. The targets we propose have potential benefits in the treatment of CNS disorders such as Alzheimer's and Parkinson's diseases. The structural features of the target molecules allow quick construction by cycloaddition of imino functionalities. This procedure has potential utility in the synthesis of a variety of other desired nitrogen-containing compounds. This approach will also be investigated of other 1-azaspirane ring systems.
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