1. The relationship between stereochemical and both, pharmacological and ADME-Tox, properties of the potent hydantoin 5-HT 7 R antagonist MF-8.
- Author
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Kucwaj-Brysz K, Latacz G, Podlewska S, Żesławska E, Handzlik J, Lubelska A, Satała G, Nitek W, and Handzlik J
- Subjects
- Animals, Binding Sites, Cell Line, Tumor, Cytochrome P-450 CYP2C9 chemistry, Cytochrome P-450 CYP2C9 metabolism, Cytochrome P-450 CYP3A Inhibitors chemical synthesis, Cytochrome P-450 CYP3A Inhibitors metabolism, Cytochrome P-450 CYP3A Inhibitors pharmacokinetics, Cytochrome P-450 CYP3A Inhibitors toxicity, Density Functional Theory, Drug Stability, Humans, Hydantoins chemical synthesis, Hydantoins metabolism, Hydantoins toxicity, Mice, Microsomes, Liver metabolism, Models, Chemical, Molecular Docking Simulation, Molecular Dynamics Simulation, Piperazines chemical synthesis, Piperazines metabolism, Piperazines toxicity, Protein Binding, Proton Magnetic Resonance Spectroscopy, Receptors, Serotonin chemistry, Receptors, Serotonin metabolism, Serotonin Antagonists chemical synthesis, Serotonin Antagonists metabolism, Serotonin Antagonists toxicity, Stereoisomerism, Hydantoins pharmacokinetics, Piperazines pharmacokinetics, Serotonin Antagonists pharmacokinetics
- Abstract
This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HT
7 R ligand with antidepressant activity on mice. The combination of DFT calculations of1 H 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-HT7 R affinity and antagonistic action, with Ki and Kb values in the range of 3-366 nM and 0.024-99 μM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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