Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors

Maria Laura Bolognesi, Andrea Cavalli, Vincenza Andrisano, Manuela Bartolini, Rita Banzi, Alessandra Antonello, Michela Rosini, Carlo Melchiorre

Research output: Contribution to journalArticle

Abstract

Ambenonium (1), an old AChE inhibitor, is endowed with an outstanding affinity and a peculiar mechanism of action that, taken together, make it a very promising pharmacological tool for the treatment of Alzheimer's disease (AD). Unfortunately, the bisquaternary structure of 1 prevents its passage through the blood brain barrier. In a search of centrally active ambenonium derivatives, we planned to synthesize tertiary amines of 1, such as 2 and 3. In addition, to add new insights into the binding mechanism of the inhibitor, we designed constrained analogues of ambenonium by incorporating the diamine functions into cyclic moieties (4-12). The biological evaluation of the new compounds has been assessed in vitro against human AChE and BChE. All tertiary amine derivatives resulted more than 1000-fold less potent than 1 and, unlike prototype, did not show any selectivity between the two enzymes. This result, because of recent findings concerning the role of BChE in AD, makes our compounds, endowed with a well-balanced profile of AChE/BChE inhibition, valuable candidates for further development. To better clarify the interactions that account for the high affinity of 1, docking simulations and molecular dynamics studies on the AChE-1 complex were also carried out.

Original languageEnglish
Pages (from-to)917-928
Number of pages12
JournalFarmaco
Volume58
Issue number9
DOIs
Publication statusPublished - Sep 1 2003

Keywords

  • Acetylcholinesterase
  • Acetylcholinesterase inhibitor
  • Alzheimer's disease
  • Ambenonium analogues
  • Butyrylcholinesterase

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmaceutical Science

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  • Cite this

    Bolognesi, M. L., Cavalli, A., Andrisano, V., Bartolini, M., Banzi, R., Antonello, A., Rosini, M., & Melchiorre, C. (2003). Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors. Farmaco, 58(9), 917-928. https://doi.org/10.1016/S0014-827X(03)00150-2