N-Skatyltryptamines—Dual 5-HT(6)R/D(2)R Ligands with Antipsychotic and Procognitive Potential

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT(1A), 5-HT(2A), 5-HT(6), and D(2) receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D(2) receptor antagonists with additional 5-HT(6)R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT(6)R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT(6)R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D(2)R antagonist function combined with 5-HT(6)R agonism, and mixed D(2)/5-HT(6)R antagonists in murine models of psychosis.