Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis

To provide a further test of the dual binding site hypothesis proposed for acetylcholinesterase (AChE) inhibitor heptylene-linked bis-(9-amino-1,2,3,4 -tetrahydroacridine) A7A, short-tether (ethylene-hexylene) homologs A2A-A6A were prepared. En route to these compounds, convenient and scaleable synth eses of useful pharmaceutical intermediate 9-chloro-1,2,3,4-tetrahydroacrid ine 3 and A7A were developed. AChE and butyrylcholinesterase (BChE) inhibit ion assays of A2A-A10A confirm that a seven methylene tether (A7A) optimize s AChE inhibition potency and AChE/BChE selectivity. Finally, these studies indicate that simultaneous binding of alkylene-linked 9-amino-1,2,3,4-tetr ahydroacridine dimers to the catalytic and peripheral sites of AChE is poss ible with a tether length as short as 5 methylenes. (C) 1999 Elsevier Scien ce Ltd. All rights reserved.