Synthesis of dual AChE/5-HT4 receptor multi-target directed ligands

Abstract

The synthesis of novel pyrrolothienopyrazines has been achieved with the aim to bring together in a sole compound both AChE inhibitory effect and 5-HT₄R agonist activity. These Multi-Target Directed Ligands might theoretically alleviate the cognitive deficit in Alzheimer disease by restoring the cholinergic activity and by promoting the non-amyloidogenic formation of sAPPα which seems detrimental to the amyloid aggregation. Some of the synthesized compounds bear for the first time these dual activities and compound 15b appears particularly potent towards both AChE and 5-HT₄R targets with IC₅₀ and K_i in nanomolar levels. Although these MTDL behave as 5-HT₄R antagonists rather than agonists, these results appear hopeful concerning the design of further MTDL with therapeutic interest in AD treatment.