Evaluation of short-tether bis-THA AChE inhibitors. A further test of the dual binding site hypothesis

Paul R. Carlier, Yi Fan Han, Ella S.H. Chow, Crystal P.L. Li, Hong Wang, Thuy Xuan Lieu, Hau Sum Wong, Yuan Ping Pang

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

To provide a further test of the dual binding site hypothesis proposed for acetylcholinesterase (AChE) inhibitor heptylene-linked bis-(9-amino-1,2,3,4-tetrahydroacridine) A7A, short-tether (ethylene-hexylene) homologs A2A-A6A were prepared. En route to these compounds, convenient and scaleable syntheses of useful pharmaceutical intermediate 9-chloro-1,2,3,4-tetrahydroacridine 3 and A7A were developed. AChE and butyrylcholinesterase (BChE) inhibition assays of A2A-A10A confirm that a seven methylene tether (A7A) optimizes AChE inhibition potency and AChE/BChE selectivity. Finally, these studies indicate that simultaneous binding of alkylene-linked 9-amino-1,2,3,4-tetrahydroacridine dimers to the catalytic and peripheral sites of AChE is possible with a tether length as short as 5 methylenes. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)351-357
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume7
Issue number2
DOIs
StatePublished - Feb 1999

ASJC Scopus subject areas

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

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