The relationship between stereochemical and both, pharmacological and ADME-Tox, properties of the potent hydantoin 5-HT7R antagonist MF-8

This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydmxy-3-(4-(2-methoxyphenyepiperazin-1-yepropyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HT7R ligand with antidepressant activity on mice. The combination of DFT calculations of H-1 NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HT7R affinity and antagonistic action, with K-i and K-b values in the range of 3-366 nM and 0.024-99 mu M, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycopmtein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities.

Automated summary

This study investigated the synthesis and evaluation of pharmacodynamic and pharmacokinetic profiles for all four stereoisomers of MF-8, a highly potent 5-HT7R ligand with antidepressant activity. The results showed significant impact of stereochemistry on 5-HT7R affinity and antagonistic action, as well as on P-glycoprotein efflux, absorption in Caco-2 model, and metabolic pathways.