Stereospecific 5-HT6 receptor antagonism by PUC-10 enhances cognitive performance: Neurobehavioral and Translational Insights

Cognitive dysfunction is a core feature of several neuropsychiatric disorders, including schizophrenia, major depressive disorder and obsessive-compulsive disorder. The 5-HT6 receptor (5-HT6R), a Gs-coupled serotonin receptor enriched in cortico-striatal circuits, is a promising target for modulating cognitive function. Here we examined the neurobehavioral and translational potential of PUC-10, a potent and selective 5-HT6R antagonist of the N-arylsulfonylindole class, which exists as R- and S-enantiomers. Binding and functional assays identified the eutomer, showing higher affinity and potency at 5-HT6R than its antipode (Ki = 2.76 nM; Kb = 15 nM). We evaluated (E)-PUC-10 and racemic PUC-10 in rats after acute and repeated administration, assessing locomotor activity and cognitive performance in the novel object recognition test. Repeated dosing of the racemate was well tolerated, producing only a transient increase in locomotor activity. Notably, (E)-PUC-10 significantly improved novel object recognition in both male and female rats compared with vehicle-treated controls. Moreover, (E)-PUC-10 at 5 mg/kg increased hippocampal expression of the lipidated autophagy marker LC3-II in male rats, consistent with the involvement of autophagy-related processes in the procognitive effects of 5-HT6R blockade. Together, these findings identify the PUC-10 eutomer and support its potential as a therapeutic candidate for cognitive impairment associated with neuropsychiatric conditions.