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 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.
Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
D D
DD
Schoepp
B G
BG
Johnson
C R
CR
Salhoff
M J
MJ
Valli
M A
MA
Desai
J P
JP
Burnett
N G
NG
Mayne
J A
JA
Monn
D000818:Animals; D000831:Animals, Newborn; D003001:Cloning, Molecular; D005576:Colforsin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000096:biosynthesis; D015290:Second Messenger Systems / Q000187:drug effects
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D018690:Excitatory Amino Acid Agonists; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D005576:Colforsin; D011392:Proline; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D009638:Norepinephrine