SYNTHESIS OF ALKYLENE LINKED BIS-THA AND ALKYLENE LINKED BENZYL-THA AS HIGHLY POTENT AND SELECTIVE INHIBITORS AND MOLECULAR PROBES OF ACETYLCHOLINESTERASE

An efficient and economical synthesis of a series of rationally design novel -1,-omega-diyldiimino)-1,2,3,4-tetrahydroacridines (omega = 7-1 0) and a second series of new analogues, mega-phenylalkylamino)-1,2,3, 4-tetrahydroacridines (omega = 4-10), is reported. Compounds in the fi rst series are found to be up to 10 000-fold more selective and 1000-f old more potent in reversibly inhibiting rat acetylcholinesterase (ACh E) than the monomer, 9-amino-1,2,3,4-tetrahydroacridine (THA). Some me mbers in the latter series (omega = 7-8) are slightly more potent than THA in inhibiting AChE but still more selective. These compounds can serve as (i) important chemical tools to evaluate the role of AChE inh ibition by THA, a clinical drug, in treating Alzheimer's disease, (ii) effective, safer and low-cost insecticides and parasiticides, (iii) p otential blockers of the K+ channel and the N-methyl-D-aspartate recep tor channel, and perhaps (iv) improved therapeutics for Alzheimer's di sease.