Document Report Card

ID: ALA1132438

Journal: J Med Chem

Title: Heterodimeric tacrine-based acetylcholinesterase inhibitors: investigating ligand-peripheral site interactions.

Authors: Carlier PR, Chow ES, Han Y, Liu J, El Yazal J, Pang YP.

Abstract: 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 peripheral site. Basic amines of differing hydrophobicity were selected as peripheral site ligands, and in each case, improvements in inhibitory potency and selectivity were seen relative to tacrine itself. AChE IC(50) values of the optimum dimers decrease significantly as the peripheral site ligand was permuted in the series ammonia > dimethylamine > 4-aminopyridine > 4-aminoquinoline > tacrine. Calculated desolvation free energies of the optimum dimers match the trend in IC(50) values, suggesting the importance of ligand hydrophobicity for effective cation-pi interaction with the peripheral site.

CiteXplore: 10514292

DOI: 10.1021/jm990224w