Dual-site binding of bivalent 4-aminopyridine- and 4-aminoquinoline-based AChE inhibitors: Contribution of the hydrophobic alkylene tether to monomerand dimer affinities

Three series of 4-aminopyridine-and 4-aminoquinoline based symmetrical biva lent acetylcholinesterase (AChE) inhibitors were prepared and compared to p reviously synthesized dimers of 9-amino-1,2,3,4-tetrahydroacridine (tacrine ). In each case significant, tether length-dependent increases in AChE inhi bition potency and selectivity (up to 3000-fold) were observed relative to the corresponding monomer, indicating dual-site binding of these inhibitors to AChE. Assay of the corresponding alkylated monomers revealed that the a lkylene tether played at least two complementary roles in the dimer series. In addition to reducing the entropy loss that occurs on binding both monom eric units of the dimer; the alkylene tether can also significantly improve potency through hydrophobic effects. (C) 1999 Elsevier Science Ltd. All ri ghts reserved.