3-(aminomethyl)piperazine-2,5-dione as a novel NMDA glycine site inhibitor from the chemical universe database GDB

Bioorg Med Chem Lett. 2009 Jul 15;19(14):3832-5. doi: 10.1016/j.bmcl.2009.04.021. Epub 2009 Apr 10.


Docking of randomly selected compounds from the chemical universe database GDB-11, which contains all organic molecules up to 11 atoms of C, N, O, F possible under consideration of simple chemical stability and synthetic feasibility rules, into the NMDA receptor glycine site (1pb7.pdb) lead to the identification of 3-(aminomethyl)piperazine-2,5-dione 3 and its close analog 5-(aminomethyl)piperazine-2,3-dione 4 as possible new ligands for this drug target, which is implicated in synaptic plasticity, neuronal development, learning and memory. Synthesis of these compounds in 4 and 6 steps, respectively, and testing by radioligand displacement assays and electrophysiological measurements in Xenopus oocytes show that while 4 is inactive, 3 is indeed an inhibitor of glycine, with an estimated K(D) of 50 microM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Computer Simulation
  • Databases, Factual
  • Diketopiperazines / chemical synthesis
  • Diketopiperazines / chemistry*
  • Diketopiperazines / pharmacology
  • Glycine / chemistry*
  • Oocytes / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Software
  • Thermodynamics
  • Xenopus laevis


  • 3-(aminomethyl)piperazine-2,5-dione
  • 5-(aminomethyl)piperazine-2,3-dione
  • Diketopiperazines
  • Receptors, N-Methyl-D-Aspartate
  • Glycine