Triquinane-based compounds as possible serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease

The recently discovered serotonin 5-HT6 receptor is a novel target for the treatment of cognitive decline associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several studies have shown that antagonism of this receptor leads to improved learning and memory. Two serotonin 5-HT6 receptor antagonists are currently in Phase II clinical trials for cognitive enhancement. Striking structural similarities between the polycyclic features of some 5-HT6 antagonists and those of the cis-syn-cis triquinane ring system led us to propose that triquinane-derived compounds may represent a novel class of 5-HT6 receptor antagonists. Using computational methodologies, we propose a structure with features that may impart potent 5-HT6 receptor antagonistic activities to the triquinane ring complex. Related compounds, once synthesized, may have possible utility in the treatment of cognitive decline associated with AD.