Selective inhibition of forskolin-stimulated cyclic AMP formation in rat hippocampus by a novel mGluR agonist, 2R,4R-4-aminopyrrolidine-2,4- dicarboxylate

Neuropharmacology. 1995 Aug;34(8):843-50. doi: 10.1016/0028-3908(95)00061-a.


Metabotropic glutamate receptors (mGluRs) are a heterogeneous family of G-protein coupled receptors that are linked to multiple second messengers in the rat hippocampus. The compound 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) has been widely used to activate this class of receptors and study their functions in situ. However, 1S,3R-ACPD acts on multiple mGluR subtypes to produce multiple alterations in second messengers. We report here that the aza-substituted analog of 1S,3R-ACPD, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), is a highly selective agonist for negatively-coupled cAMP-linked mGluRs in the rat hippocampus, with similar potency in mGluR2 expressing cells. 1S,3R-ACPD decreases forskolin-stimulated cAMP formation, increases basal cAMP formation, and increases phosphoinositide hydrolysis in the rat hippocampus. However, 2R,4R-APDC inhibited forskolin-stimulated cAMP, but had none of the other activities of 1S,3R-ACPD. Furthermore, 2R,4R-APDC had no measurable ionotropic glutamate receptor affinity in rat hippocampus, as indicated by lack of effects on basal and glutamate agonist-evoked [3H]norepinephrine release. 2R,4R-APDC also inhibited forskolin-stimulated cAMP formation in human mGluR2 expressing cells with about three-fold greater potency than 1S,3R-ACPD, but unlike 1S,3R-ACPD, showed no appreciable activation of phosphoinostide hydrolysis in human mGluR1 alpha expressing cells. Thus, 2R,4R-APDC should be a useful pharmacological agent to explore the functions of mGluRs coupled to inhibition of adenylate cyclase.

MeSH terms

  • Animals
  • Animals, Newborn
  • Cloning, Molecular
  • Colforsin / antagonists & inhibitors*
  • Colforsin / pharmacology
  • Cyclic AMP / biosynthesis*
  • Excitatory Amino Acid Agonists / pharmacology*
  • Female
  • GTP-Binding Proteins / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Humans
  • In Vitro Techniques
  • Male
  • Norepinephrine / metabolism
  • Phosphatidylinositols / metabolism
  • Proline / analogs & derivatives*
  • Proline / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / biosynthesis
  • Second Messenger Systems / drug effects


  • 4-aminopyrrolidine-2,4-dicarboxylic acid
  • Excitatory Amino Acid Agonists
  • Phosphatidylinositols
  • Receptors, Metabotropic Glutamate
  • Colforsin
  • Proline
  • Cyclic AMP
  • GTP-Binding Proteins
  • Norepinephrine