The Importance of Stereochemistry in 5-HT7R Modulation─A Case Study of Hydantoin Derivatives

Abstract

Serotonin 5-HT₇ receptor (5-HT₇R), one of the most recently discovered members of the serotonergic system, has become a promising target in the search for central nervous system disorders. Despite the number of preclinical results, none of the selective 5-HT₇R agents has been approved; therefore, the clinical significance of this protein has not been confirmed yet. Recently, we described very promising, selective, and highly potent hydantoin-derived 5-HT₇R antagonists with confirmed antidepressant activity in vivo and a very good ADMET profile; however, they have been tested in behavioral studies as racemates. In this work, the synthesis of optically pure hydantoin-derived 5-HT₇R agents using cost-effective, classical methods has been presented for the first time. X-ray crystallographic analysis confirmed the absolute configuration on both stereogenic centers and allowed for the elucidation of the mechanism of introduction of epichlorohydrin into the hydantoin N3-position. The radioligand binding results showed a clear configuration preference for 5-HT₇R affinity. The molecular modeling results further indicated the key interaction responsible for lower affinity (with amino acid I3 × 29). Finally, the comparison of the antidepressant and anxiolytic effects of racemates versus stereoisomers suggests an influence of additional, apart from the action on 5HT₇R, factors responsible for the activity in vivo, which is worthy of deeper insight within further studies.