Chemical puzzles in the search for new, flexible derivatives of lurasidone as antipsychotic drugs

In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D₂, 5-HT_1A, 5-HT_2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT₆ and 5-HT₇ receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT₇R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D₂, D₃, 5-HT_1A, 5-HT_2A, 5-HT₇ receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT₇R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT₇R and increased affinity for 5-HT₆R. For this purpose, we chose aflexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT₆R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i - a multifunctional ligand showing moderate affinity for 5-HT₆R and threefold lower for 5-HT₇R. In the paper, we discuss some of the observed dependencies regarding 5-HT₆/5-HT₇R affinity using molecular docking methods.