3-(aminomethyl)piperazine-2,5-dione as a novel NMDA glycine site inhibitor from the chemical universe database GDB.
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.
Nguyen
Kong Thong
KT
Department of Chemistry and Biochemistry, University of Berne, Berne, Switzerland.
Luethi
Erika
E
Syed
Salahuddin
S
Urwyler
Stephan
S
Bertrand
Sonia
S
Bertrand
Daniel
D
Reymond
Jean-Louis
JL
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005998:Glycine / Q000737:chemistry*; D009865:Oocytes / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012984:Software; D013816:Thermodynamics; D014982:Xenopus laevis
C544464:3-(aminomethyl)piperazine-2,5-dione; C544466:5-(aminomethyl)piperazine-2,3-dione; D054659:Diketopiperazines; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine