Heterodimeric tacrine-based acetylcholinesterase inhibitors: Investigating ligand-peripheral site interactions

Paul R. Carlier, Ella S.H. Chow, Yifan Han, Jing Liu, Jamal El Yazal, Yuan Ping Pang

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132 Scopus citations


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 IC50 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 IC50 values, suggesting the importance of ligand hydrophobicity for effective cation-π interaction with the peripheral site.

Original languageEnglish (US)
Pages (from-to)4225-4231
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number20
StatePublished - Oct 7 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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