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Issue 5, 2012
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Synthesis of dual AChE/5-HT4 receptor multi-target directed ligands

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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 Ki 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.

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

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Publication details

The article was received on 04 Mar 2012, accepted on 20 Mar 2012 and first published on 23 Mar 2012


Article type: Concise Article
DOI: 10.1039/C2MD20063E
Citation: Med. Chem. Commun., 2012,3, 627-634
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    Synthesis of dual AChE/5-HT4 receptor multi-target directed ligands

    C. Lecoutey, C. Rochais, D. Genest, S. Butt-Gueulle, C. Ballandonne, S. Corvaisier, F. Dulin, A. Lepailleur, J. Sopkova-de Oliveira Santos and P. Dallemagne, Med. Chem. Commun., 2012, 3, 627
    DOI: 10.1039/C2MD20063E

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