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

Bioorg Chem. 2021 Jan:106:104466. doi: 10.1016/j.bioorg.2020.104466. Epub 2020 Nov 10.

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-HT7R ligand with antidepressant activity on mice. The combination of DFT calculations of 1H 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 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.

Keywords: 5-HT(7)R ligands; ADMET; Arylpiperazine; DFT; Docking; Hydantoin; Serotonin receptors; Stereoisomers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / pharmacokinetics*
  • Hydantoins / toxicity
  • Mice
  • Microsomes, Liver / metabolism
  • Models, Chemical
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Piperazines / chemical synthesis
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics*
  • Piperazines / toxicity
  • Protein Binding
  • Proton Magnetic Resonance Spectroscopy
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacokinetics*
  • Serotonin Antagonists / toxicity
  • Stereoisomerism

Substances

  • 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin
  • Cytochrome P-450 CYP3A Inhibitors
  • Hydantoins
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor
  • Cytochrome P-450 CYP2C9