Background: in recent years, considerable research efforts have focused on the role of serotonin in various pathological states, as well as on the identification of the respective serotonin receptors involved. Among serotonin receptors, 5-HT6R is the most recently discovered sub-class. Despite the development of multiple selective ligands, the functional role of this receptor has thus far remained elusive. Available in vitro and in vivo evidence indicates that 5-HT6 receptor antagonists can produce promnesic or antiamnesic effects in a variety of contexts, including memory formation, age-related cognitive impairments, and memory deficits associated with conditions such as schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Recent progress in the understanding of the 5-HT6 receptor and its ligands includes a suggested constitutive activity for the receptor, development of a number of multimodal small molecule ligands, and re-classification of many selective antagonists as pseudo-selective compounds. In light of these findings, the observed pharmacological effects produced by 5-HT6R ligands are now properly assigned to a spectrum of related biological targets, rather than to an individual receptor.Objective: this systematic review has attempted to properly summarize available data describing the pharmacological profiles of 5-H6R ligands. These ligands are grouped into three different categories based on their specific mode of action: multimodal, pseudo-selective and selective ligands.
Conclusion: it has been established that almost all of the drug candidates currently being evaluated in clinical trials share a multimodal mode of action or pseudo-selective binding. Recently, Asenapine maleate, a multimodal atypical antipsychotic, has been released onto the market under the brand name Saphris. In recent years, a variety of selective 5-H6R ligands have been synthesized and biologically evaluated.