ISSN:
1573-501X
Keywords:
2
;
5-piperazinedione
;
acetylcholinesterase
;
combinatorial library
;
inhibition
;
molecular modeling
;
multiple parallelsynthesis
;
selectivity
;
solid phase
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The potentiation of central cholinergic activity has beenproposed as a therapeutic approach for improving cognitivefunction in patients with Alzheimer's disease. Increasingthe acetylcholine concentration in brain by modulatingacetylcholinesterase (AChE) activity is among the mostpromising strategies. We have used a combinatorial approachto identify different 2,5-piperazinediones (DKP) with AChEinhibitory activity. Our goal was to find inhibitorsexhibiting high AChE/BuChE (butyrylcholinesterase)selectivity, in order to reduce the undesirable sideeffects elicited by most of the inhibitors that have beendeveloped to date. Screening of a DKP library constructedon solid-phase using the multiple parallel synthesisformat, resulted in the identification of several compoundswith moderate efficacy on AChE. In particular, DKP-80had an IC50 = 2.2 μM with no significant inhibitoryactivity on BuChE. Moreover, estimated values of Clog P andlog BB for the most active compounds fulfilled thebioavailability requirements for enzyme inhibitors actingon the central nervous system. In order to understand theinhibitory properties of the ligand at the molecular level,molecular dynamics simulations were computed on DKP-80 complexed to AChE, and the most relevant bindinginteractions of this inhibitor to the active center of theenzyme were characterized. Overall the present resultsindicate that the DKP-based compounds identified are novelAChE inhibitors which may be considered likely leadcompounds for further development of drug candidatesagainst Alzheimer's disease.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1016230600162
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