The Importance\nof Stereochemistry in 5‑HT<sub>7</sub>R ModulationA\nCase Study of Hydantoin Derivatives

Serotonin 5-HT<sub>7</sub> receptor (5-HT<sub>7</sub>R), one of\nthe most recently discovered members of the serotonergic system, has\nbecome a promising target in the search for central nervous system\ndisorders. Despite the number of preclinical results, none of the\nselective 5-HT<sub>7</sub>R agents has been approved; therefore, the\nclinical significance of this protein has not been confirmed yet.\nRecently, we described very promising, selective, and highly potent\nhydantoin-derived 5-HT<sub>7</sub>R antagonists with confirmed antidepressant\nactivity <i>in vivo</i> and a very good ADMET profile; however,\nthey have been tested in behavioral studies as racemates. In this\nwork, the synthesis of optically pure hydantoin-derived 5-HT<sub>7</sub>R agents using cost-effective, classical methods has been presented\nfor the first time. X-ray crystallographic analysis confirmed the\nabsolute configuration on both stereogenic centers and allowed for\nthe elucidation of the mechanism of introduction of epichlorohydrin\ninto the hydantoin N3-position. The radioligand binding results showed\na clear configuration preference for 5-HT<sub>7</sub>R affinity. The\nmolecular modeling results further indicated the key interaction responsible\nfor lower affinity (with amino acid I3 × 29). Finally, the comparison\nof the antidepressant and anxiolytic effects of racemates versus stereoisomers\nsuggests an influence of additional, apart from the action on 5HT<sub>7</sub>R, factors responsible for the activity <i>in vivo</i>, which is worthy of deeper insight within further studies.