Synthesis, in Silico and in Vitro Study on Phase I Metabolism of the Potent 5-Ht7/5-Ht1a/D2 Receptor Ligand: 4-Fluoron -(1-{2-[2-(Methylsulfanyl)- Phenoxy]Ethyl}Pyrrolidin-3-Yl) Benzene Sulfonamide

In the present study we analyze the synthesis as well as biotransformation pathways and metabolic stability of 4-fluoro- N -(1-{2-[2-(methylsulfanyl)phenoxy]ethyl}pyrrolidin-3-yl) benzene sulfonamide - thioether compound 5, with the affinity for several subtypes of the serotonin and dopamine receptor. Studies were conducted in vitro on liver microsomes from three species - mouse, rat, and human. The biotransformation was analyzed using liquid chromatography coupled with mass spectrometry. Two major metabolites (M1 and M2) - products of S-oxidation of the parent molecule - were generated both by in silico and in vitro methods. Use of three species allowed us to determine the interspecies differences in metabolic stability of tested compound. Two parameters, t(0.5) and Cl-int , were calculated. Compound 5 was the most stable in human liver microsomes. Results are useful for understanding the interspecies differences in metabolism of the serotonin and dopamine receptor ligand associated with sulfur atom.