title: Design, synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors.
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.
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000549:Ambenonium Chloride / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D000549:Ambenonium Chloride; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase