Procognitive Potential of Neuroprotective Triazine 5-HT6 Receptor Antagonists Tested on Chronic Activity In Vivo in Rats: Computer-Aided Insight into the Role of Chalcogen-Differences on the Pharmacological Profile

Among serotonin receptors, the 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. This study aimed to extend the body of preclinical research on two naphthyl-derived methylpiperazine-1,3,5-triazine analogues with thioether (WA-22) or Se-ether (PPK-32) linkers, the newly described compounds having high affinity and selectivity for 5-HT6 receptors and drug-like parameters in vitro. Thus, crystallography-supported deeper insight into their chemical properties, the comparison of their neuroprotective and pharmacokinetic profiles, and especially their impact on memory disturbances after chronic administration to rats were investigated. As a result, the chronic administration of WA-22 completely reversed (+)MK-801-induced memory disturbances evaluated in the novel object recognition test (NORT) in rats. The pharmacokinetic and biochemical results support the notion that this 1,3,5-triazine 5-HT6 receptor ligand could offer a promising therapeutic tool in CNS-related disorders. The selenium compound PPK-32, with a similar range of activity at acute administration, has shown even broader neuroprotective profiles, especially at the genetic level. However, for therapeutic use, its weaker pharmacokinetics (stability), which is a probable limit for action upon chronic administration, would require improvement, e.g., by an appropriate formulation.