Potent antagonists at the L-AP4- and (1S,3S)-ACPD-sensitive presynaptic metabotropic glutamate receptors in the neonatal rat spinal cord

Neuropharmacology. 1996;35(8):1029-35. doi: 10.1016/s0028-3908(96)00048-2.


In this report we describe the actions of two novel compounds, (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) and (S)-alpha-ethylglutamate (EGLU), which are potent antagonists at two types of presynaptic metabotropic glutamate (mGlu) receptors in the neonatal rat spinal cord. Selective activation of these receptors by L-2-amino-4-phosphonobutyrate (L-AP4) or (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3S)-ACPD) results in the depression of the monosynaptic component of the dorsal root-evoked ventral root potential (DR-VRP). CPPG produces rightward parallel shifts of the dose-response curves for both L-AP4- and (1S,3S)-ACPD, with Schild slope in each case close to unity, consistent with a competitive mechanism of antagonism. CPPG is the most potent antagonist yet described for both L-AP4- and (1S,3S)-ACPD-sensitive presynaptic mGlu receptors but displays a 30-fold selectivity for the L-AP4-sensitive receptor over the (1S,3S)-ACPD-sensitive receptor (KD values 1.7 microM and 53 microM, respectively). EGLU, on the other hand, is selective for the (1S,3S)-ACPD-sensitive receptor, displaying little or no activity at the L-AP4-sensitive site. EGLU produces a rightward parallel shift of the dose-response curve to (1S,3S)-ACPD, with Schild slope close to unity, again indicative of a competitive mode of antagonism (KD 66 microM). Both CPPG and EGLU displayed only weak or no antagonist activity at postsynaptic metabotropic and ionotropic glutamate receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / pharmacology*
  • Animals
  • Animals, Newborn
  • Cycloleucine / analogs & derivatives*
  • Cycloleucine / antagonists & inhibitors
  • Cycloleucine / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology*
  • Glutamates / chemical synthesis
  • Glutamates / pharmacology*
  • Glycine / analogs & derivatives*
  • Glycine / chemical synthesis
  • Glycine / pharmacology
  • N-Methylaspartate / pharmacology
  • Rats
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Presynaptic / agonists
  • Receptors, Presynaptic / antagonists & inhibitors*
  • Spinal Cord / metabolism*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Aminobutyrates
  • Excitatory Amino Acid Agonists
  • Glutamates
  • Receptors, Metabotropic Glutamate
  • Receptors, Presynaptic
  • cyclopropyl-4-phosphonophenylglycine
  • Cycloleucine
  • alpha-ethylglutamic acid
  • 1-amino-1,3-dicarboxycyclopentane
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • 2-amino-4-phosphonobutyric acid
  • Glycine