Serotonin 5‑HT₆ Receptor Antagonists for the Treatment of Cognitive Deficiency in Alzheimer’s Disease

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.