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

Research output: Contribution to journalArticle

125 Citations (Scopus)

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 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
Volume42
Issue number20
DOIs
StatePublished - Oct 7 1999

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Cholinesterase Inhibitors
Acetylcholinesterase
Hydrophobicity
Ligands
Hydrophobic and Hydrophilic Interactions
Dimers
Inhibitory Concentration 50
Tacrine
4-Aminopyridine
Ammonia
Free energy
Amines
Cations

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Heterodimeric tacrine-based acetylcholinesterase inhibitors : Investigating ligand-peripheral site interactions. / Carlier, Paul R.; Chow, Ella S H; Han, Yifan; Liu, Jing; El Yazal, Jamal; Pang, Yuan-Ping.

In: Journal of Medicinal Chemistry, Vol. 42, No. 20, 07.10.1999, p. 4225-4231.

Research output: Contribution to journalArticle

Carlier, Paul R. ; Chow, Ella S H ; Han, Yifan ; Liu, Jing ; El Yazal, Jamal ; Pang, Yuan-Ping. / Heterodimeric tacrine-based acetylcholinesterase inhibitors : Investigating ligand-peripheral site interactions. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 20. pp. 4225-4231.
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