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J Med Chem. 2014 Sep 11;57(17):7160-81. doi: 10.1021/jm5003952. Epub 2014 Jun 3.

Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease.

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Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid , E-28040 Madrid, Spain.


Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.

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