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

Yifan Han, Crystal P.L. Li, Ella Chow, Hong Wang, Yuan Ping Pang, Paul R. Carlier

Research output: Journal article publicationJournal articleAcademic researchpeer-review

42 Citations (Scopus)


Three series of 4-aminopyridine-and 4-aminoquinoline based symmetrical bivalent acetylcholinesterase (AChE) inhibitors were prepared and compared to previously synthesized dimers of 9-amino-1,2,3,4-tetrahydroacridine (tacrine). In each case significant, tether length-dependent increases in AChE inhibition 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 alkylene tether played at least two complementary roles in the dimer series. In addition to reducing the entropy loss that occurs on binding both monomeric units of the dimer, the alkylene tether can also significantly improve potency through hydrophobic effects. (C) 1999 Elsevier Science Ltd.
Original languageEnglish
Pages (from-to)2569-2575
Number of pages7
JournalBioorganic and Medicinal Chemistry
Issue number11
Publication statusPublished - 1 Nov 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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