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

Article Details

Citation

Copy to clipboard

Bolognesi ML, Cavalli A, Andrisano V, Bartolini M, Banzi R, Antonello A, Rosini M, Melchiorre C

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

Farmaco. 2003 Sep;58(9):917-28.

PubMed ID

13679187 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ambenonium	Acetylcholinesterase	Protein	Humans	Yes	Inhibitor	Details