PREPARATION AND SCREENING AGAINST ACETYLCHOLINESTERASE OF A NONPEPTIDE INDEXED COMBINATORIAL LIBRARY

A combinatorial library composed from nine alcohols and six isocyanates to formally generate 54 carbamates has been designed, prepared, and screened against acetylcholinesterase from the electric eel. In order to deduce the most active member of the library, it was prepared as 15 sublibraries in which one of the reacting components was fixed and the other reactants were used as an equimolar mixture. The product mixtures were tested and their activities used as ''indices'' to the rows or columns of a two-dimensional matrix reflecting the activities of individual carbamates. A number of carbamates in the most active row and column were synthesized and assayed, demonstrating that the most active cell in the matrix could be identified by the sublibrary synthesis procedure. Other methods for generating large libraries of molecules for biological screening that have recently been developed have relied on a covalent attachment between library members and a label to identify the active components. Indexed libraries offer the advantage that they can be prepared from any class of compounds composed from multiple subunits and that any type of assay (binding, enzyme inhibition, agonism/antagonism, cell-based, or even whale organism assays for biological activity) can be used because all compounds are generated in a free form.