Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT(4) receptor activation (RS67333) on object recognition in mice.
Behavioural Brain Research. 2012-04-01; 230(1): 304-308
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1. Behav Brain Res. 2012 Apr 21;230(1):304-8. doi: 10.1016/j.bbr.2012.02.012. Epub
2012 Feb 14.
Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT(4)
receptor activation (RS67333) on object recognition in mice.
Freret T(1), Bouet V, Quiedeville A, Nee G, Dallemagne P, Rochais C, Boulouard M.
(1)Université de Caen Basse, Normandie, EA 4259 – Groupe Mémoire & Plasticité
comportementale, F-14032 Caen, France.
Facing inefficiency of current treatments to cure Alzheimer disease (AD), a
pharmacological approach is now emerging on the assumption that a single compound
may be able to hit multiple targets, namely Multi-Target-Directed Ligands
(MTDLs). Displaying numerous advantages, several MTDL for AD have been recently
described but none associating an inhibition of AChE and an activation of
5-HT(4)R. The aim of this study was to validate the concept of a synergistic
action of these two targets on episodic-like memory performances in mice. Among
potent molecules, RS67333, a reference 5-HT(4)R agonist and donepezil (DNPZ), a
reference acetylcholinesterase inhibitor, have been particularly chosen because
of their close chemical structure. Administered separately, RS67333 (0.3 and
1mg/kg) and DNPZ (1mg/kg) improved recognition performances compared to saline
treated animals but not with lower doses. Co-administration of subactive doses of
RS67333 (0.1mg/kg) and DNPZ (0.3mg/kg) improved memory, moreover, this
improvement is prevented if a 5-HT(4)R antagonist (GR125487, 10mg/kg) is also
administered. Activation of 5-HT(4)R combined with inhibition of AChE with
subactive doses of RS67333 and of DNPZ has synergistic effects on memory
performances in mice. These molecules having close chemical structures, the
synergistic effect of their combination affords new hope to chemist for the
synthesis of MTDL.
Copyright © 2012 Elsevier B.V. All rights reserved.
PMID: 22348892 [Indexed for MEDLINE]