Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT4 receptor activation (RS67333) on object recognition in mice

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-HT4R. 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-HT4R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1 mg/kg) and DNPZ (1 mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1 mg/kg) and DNPZ (0.3 mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT4R antagonist (GR125487, 10 mg/kg) is also administered. Activation of 5-HT4R 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.

► Single administration of high doses of RS67333 and donepezil improves object recognition memory.
► Combined administration of subactive doses of RS67333 and donepezil has synergetic effect.
► Merging the frameworks of RS67333 and donepezil can solve pitfalls of chemical synthesis of MTDLs.