This application process to develop new organic synthesis methodology that will allow compounds with potential biological (primarily neurological) activity to be prepared in sufficient quantities for detailed biological evaluations. Exploratory studies of new ring forming reactions, complex molecule total syntheses, and collaborative pharmacological studies of selected total synthesis targets are proposed. The primary health significance of the research outlined in this application is the potentially powerful new ring construction methodology to be developed. It is not our aim to discover new drugs, but rather to define versatile new organic synthesis tools to enable such discoveries in the future. A secondary health significance of the research proposed in this application derives from the biological activity (primarily neurological) of our synthesis targets. The studies proposed for the NS-12389-18-22 project years focus on developing """"""""pinacol-terminated"""""""" cationic cyclizations (discovered during the current NS project period) for the efficient synthesis of a variety of complex heterocycles and carbocycles. Our successful program to exploit the """"""""aza-Cope-Mannich"""""""" reaction (discovered under the auspices of NS-12389) as the key element of a broadly applicable strategy for alkaloid synthesis will also be continued. Total synthesis targets include the Strychnos alkaloids (plus minus)-akuammicine, (plus minus)-norfluorocurarine and (-)- strychnine; the methanomorphanthridine alkaloids (+)-megellaninone and the polyether marine sesquiterpene natural product (-)-kumausallene. A series of branched chain C-nucleoside analogs and potential centrally acting muscarinic agonists will be prepared and biologically evaluated. Muscarinic agonists that effect muscarinic receptors in the cortex are of potential use in treating cognitive disorders such as Alzheimer's disease. Strychnos alkaloids exhibit powerful neurological activities and members of this group are among the most paralytic neuromuscular blocking agents known today. Our collaborative studies of new NMDA receptor antagonists (prepared during the current NS grant period) will also be continued. Such antagonists are of potential use in the treatment of several neurodegenerative diseases.
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