Antagonist pharmacology of metabotropic glutamate receptors coupled to phospholipase D activation in adult rat hippocampus: Focus on (2R,1 ' S,2 ' R,3 ' S)-2-(2 '-carboxy-3 '-phenylcyclopropyl)glycine versus 3,5-dihydroxyphenylglycine

Metabotropic glutamate (mGlu) receptors coupled to phospholipase D (PLD) ap pear to be distinct from any known mGlu receptor subtype linked to phosphol ipase C or adenylyl cyclase. The availability of antagonists is necessary f or understanding the role of these receptors in the central nervous system, but selective ligands have not yet been identified. In a previous report, we observed that 3,5-dihydroxyphenylglycine (3,5-DHPG) inhibits the PLD res ponse induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in adult rat hippocampal slices. We now show that the antagonist action of 3,5-DHPG (IC 50 = 70 mu M) was noncompetitive in nature and nonselective, because the dr ug was also able to reduce PLD activation elicited by 100 mu M norepinephri ne and 1 mM histamine. In the search for a selective and more potent antago nist, we examined the effects of sixteen stereoisomers of 2-(2'-carboxy-3'- phenylcyclopropyl)glycine (PCCG) on the PLD-specific transphosphatidylation reaction resulting in the formation of [H-3]phosphatidylethanol. The (2R,1 'S,2'R,3'S)-PCCG stereoisomer (PCCG-13) antagonized the formation of [H-3]p hosphatidylethanol induced by 100 mu M (1S,3R)-1-aminocyclopentan-1,3-dicar boxylate in a dose-dependent manner and with a much lower IC,, value (25 nM ) compared with 3,5-DHPG. In addition, increasing concentrations of PCCG-13 were able to shift to the right the agonist dose-response curve but had no effect when tested on other receptors coupled to PLD. The potent, selectiv e, and competitive antagonist PCCG-13 may represent an important tool for e lucidating the role of PLD-coupled mGlu receptors in adult hippocampus.