Exploration of phenyl-spaced 2-amino-(5-9)-phosphonoalkanoic acids as competitive N-methyl-D-aspartic acid antagonists

J Med Chem. 1989 Jul;32(7):1580-90. doi: 10.1021/jm00127a030.


To investigate the preferred spatial relationship of the distal phosphonic acid to the alpha-amino acid group of the established competitive N-methyl-D-aspartic acid (NMDA) antagonists APH (1) and APV (2), we have prepared a series of ortho-, meta-, and para-substituted (phosphonoalkyl)phenylglycine and -phenylalanine derivatives. With use of a [3H]CPP receptor binding assay, significant binding activity was observed to be critically dependent on both the position of substitution and length of alkyl spacing groups. Two compounds, 4-(phosphonomethyl)-phenylglycine (6, PD 129635) and 3-(phosphonomethyl)phenylalanine (15, PD 130527), displayed receptor-binding affinity comparable to that of APH. Like APH, these compounds were also effective in antagonizing both the proconvulsant and lethal action of NMDA-administered retrobulbar in the mouse. Data are also provided which compare directly the binding efficacy of these compounds against that disclosed recently for the related NMDA antagonist 18 (NPC 451). A preliminary comparison of the structures showing good receptor-binding affinity and in vivo antagonist activity suggests that the NMDA receptor prefers a "folded" rather than "extended" conformation.

MeSH terms

  • Amino Acids / pharmacology*
  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / antagonists & inhibitors
  • Chemical Phenomena
  • Chemistry
  • Male
  • Mice
  • N-Methylaspartate
  • Organophosphorus Compounds / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter / metabolism


  • Amino Acids
  • Organophosphorus Compounds
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter
  • Aspartic Acid
  • N-Methylaspartate