Synthesis of spiro-2,6-dioxopiperazine and spiro-2,6-dioxopyrazine scaffolds using amino acids in a three-component reaction to generate potential Sigma-1 (σ 1) receptor selective ligands

Eur J Med Chem. 2019 Feb 15;164:241-251. doi: 10.1016/j.ejmech.2018.12.048. Epub 2018 Dec 22.

Abstract

A library-friendly approach to generate new scaffolds is decisive for the development of molecular probes, drug like molecules and preclinical entities. Here, we present the design and synthesis of novel heterocycles with spiro-2,6-dioxopiperazine and spiro-2,6-pyrazine scaffolds through a three-component reaction using various amino acids, ketones, and isocyanides. Screening of select compounds over fifty CNS receptors including G-protein coupled receptors (GPCRs), ion channels, transporters, and enzymes through the NIMH psychoactive drug screening program indicated that a novel spiro-2,6-dioxopyrazine scaffold, UVM147, displays high binding affinity at sigma-1 (σ1) receptor in the nanomolar range. In addition, molecular docking of UVM147 at the human σ1 receptor have shown that it resides in the same binding site that was occupied by the ligand 4-IBP used to obtain a crystal structure of the human sigma-1 (σ1) receptor.

Keywords: Amino acids; Bis-nucleophile; Multicomponent reaction; Sigma-1 receptor; Spiro-2,6-dioxopyrazine.

MeSH terms

  • Amino Acids / chemistry
  • Binding Sites
  • Crystallography, X-Ray
  • Ligands
  • Molecular Docking Simulation
  • Perazine / chemical synthesis
  • Perazine / metabolism*
  • Protein Binding
  • Pyrazines / chemical synthesis
  • Pyrazines / metabolism*
  • Receptors, sigma / metabolism*
  • Spiro Compounds / chemical synthesis

Substances

  • Amino Acids
  • Ligands
  • Pyrazines
  • Receptors, sigma
  • Spiro Compounds
  • sigma-1 receptor
  • Perazine