Synthesis, Molecular Modeling Studies, and Preliminary Pharmacological Characterization of All Possible 2-(2'-sulfonocyclopropyl)glycine Stereoisomers as Conformationally Constrained L-homocysteic Acid Analogs

J Med Chem. 2007 Sep 20;50(19):4630-41. doi: 10.1021/jm070322e. Epub 2007 Aug 29.

Abstract

Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Line
  • Cricetinae
  • Crystallography, X-Ray
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology
  • Glycine / analogs & derivatives*
  • Glycine / chemical synthesis*
  • Glycine / chemistry
  • Glycine / pharmacology
  • Homocysteine / analogs & derivatives*
  • Homocysteine / chemical synthesis
  • Homocysteine / chemistry
  • Homocysteine / pharmacology
  • In Vitro Techniques
  • Models, Molecular*
  • Molecular Conformation
  • Principal Component Analysis
  • Rats
  • Receptors, AMPA / metabolism
  • Receptors, Kainic Acid / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Thermodynamics

Substances

  • Cyclopropanes
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Sulfones
  • Homocysteine
  • homocysteic acid
  • Glycine