Heterodimeric tacrine-based acetylcholinesterase inhibitors: Investigatingligand-peripheral site interactions

Dimeric acetylcholinesterase (AChE) inhibitors containing a single 9-amino- 1,2,3,4-tetrahydroacridine (tacrine) unit were constructed in an effort to further delineate structural requirements for optimal binding to the AChE p eripheral site. Basic amines of differing hydrophobicity were selected as p eripheral site ligands, and in each case, improvements in inhibitory potenc y and selectivity were seen relative to tacrine itself. AChE IC50 values of the optimum dimers decrease significantly as the peripheral site ligand wa s permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-amin oquinoline > tacrine. Calculated desolvation free energies of the optimum d imers match the trend in IC50 values, suggesting the importance of ligand h ydrophobicity for effective cation-pi interaction with the peripheral site.