alpha-Methyl derivatives of serine-O-phosphate as novel, selective competitive metabotropic glutamate receptor antagonists

Neuropharmacology. 1996 Jun;35(6):637-42. doi: 10.1016/0028-3908(96)84635-1.


The antagonist selectivity and potency of two novel serine-O-phosphate derivatives (RS)-alpha-methylserine-O-phosphate (MSOP) and the monophenylester (RS)-alpha-methylserine-O-phosphate monophenyl-phosphoryl ester (MSOPPE) was investigated against L-2-amino-4-phosphonobutyrate (L-AP4)- and (1S,3S)-1-aminocyclopentane-1, 3-dicarboxylate (ACPD)-induced depressions of the monosynaptic excitation of neonatal rat motoneurones, mediated via metabotropic glutamate receptors (mGLuRs). MSOP was shown to be a selective antagonist for the L-AP4-sensitive presynaptic mGluR, displaying an apparent KD of 51 microM, compared to > 700 microM for the (1S,3S)-ACPD-sensitive presynaptic mGluR. In contrast, MSOPPE displayed antagonist activity at both presynaptic mGluR, with a three times greater selectivity for the (1S,3S)-ACPD-sensitive receptor over the L-AP4-sensitive mGluR (apparent KD values 73 microM and 221 microM, respectively). Therefore, on addition of an alpha-methyl group to the mGluR agonist serine-O-phosphate, we have developed an mGluR antagonist which is selective for the presynaptic L-AP4-sensitive receptor. In contrast, monoesterification of MSOP to give the monophenylphosphoryl ester (MSOPPE), confers a degree of selectivity for the (1S,3S)-ACPD-over the L-AP4-sensitive presynaptic mGluR. Neither MSOP nor MSOPPE had any activity on either postsynaptic mGLuRs or ionotropic receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Motor Neurons / drug effects*
  • N-Methylaspartate / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Serine / analogs & derivatives*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Receptors, Metabotropic Glutamate
  • Serine
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid