Characterization of l-Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N-Methyl-d-aspartate Receptor Modulators Based on Its Backbone

ACS Chem Neurosci. 2017 Aug 16;8(8):1724-1734. doi: 10.1021/acschemneuro.7b00036. Epub 2017 May 30.


l-Theanine (or l-γ-N-ethyl-glutamine) is the major amino acid found in Camellia sinensis. It has received much attention because of its pleiotropic physiological and pharmacological activities leading to health benefits in humans, especially. We describe here a new, easy, efficient, and environmentally friendly chemical synthesis of l-theanine and l-γ-N-propyl-Gln and their corresponding d-isomers. l-Theanine, and its derivatives obtained so far, exhibited partial coagonistic action at N-methyl-d-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons. This activity was retained on NMDA receptors expressed in Xenopus oocytes. In addition, both GluN2A and GluN2B containing NMDA receptors were equally modulated by l-theanine. The stereochemical change from l-theanine to d-theanine along with the substitution of the ethyl for a propyl moiety in the γ-N position of l- and d-theanine significantly enhanced the biological efficacy, as measured on cultured hippocampal neurons. l-Theanine structure thus represents an interesting backbone to develop novel NMDA receptor modulators.

Keywords: GluN2A; GluN2B; NMDA receptors; Xenopus oocytes; expression; hippocampal neurons; intracellular Ca2+ homeostasis; l-Theanine; l-γ-N-propyl-glutamine; microwave-assisted organic synthesis (MAOS).

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Excitatory Amino Acid Agonists / chemical synthesis
  • Excitatory Amino Acid Agonists / pharmacology
  • Glutamates / metabolism
  • Glutamic Acid / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oocytes
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Xenopus
  • gamma-Aminobutyric Acid / metabolism


  • Excitatory Amino Acid Agonists
  • Glutamates
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • theanine
  • Calcium