SELECTIVE-INHIBITION OF FORSKOLIN-STIMULATED CYCLIC-AMP FORMATION IN RAT HIPPOCAMPUS BY A NOVEL MGLUR AGONIST, 2R,4R-4-AMINOPYRROLIDINE-2,4-DICARBOXYLATE

Metabotropic glutamate receptors (mGluRs) are a heterogeneous family o f G-protein coupled receptors that are linked to multiple second messe ngers in the rat hippocampus. The compound 1S,3R-1-aminocyclopentane-1 ,3-dicarboxylic acid (1S,3R-ACPD) has been widely used to activate thi s 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 o f 1S,3R-ACPD, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), is a highly selective agonist for negatively-coupled cAMP-linked mGlu Rs in the rat hippocampus, with similar potency in mGluR2 expressing c ells. 1S,3R-ACPD decreases forskolin-stimulated cAMP formation, increa ses basal cAMP formation, and increases phosphoinositide hydrolysis in the rat hippocampus. However, 2R,4R-APDC inhibited forskolin-stimulat ed cAMP, but had none of the other activities of IS,3R-ACPD. Furthermo re, 2R,4R-APDC had no measurable ionotropic glutamate receptor affinit y in rat hippocampus, as indicated by lack of effects on basal and glu tamate agonist-evoked [H-3]norepinephrine release. 2R,4R-APDC also inh ibited forskolin-stimulated cAMP formation in human mGluR2 expressing cells with about three-fold greater potency than 1S,3R-ACPD, but unlik e 1S,3R-ACPD, showed no appreciable activation of phosphoinostide hydr olysis 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.