Vol. 55, Issue 4, 699-707, April 1999

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

Serenella Albani-Torregrossa, Sabina Attucci, Maura Marinozzi, Roberto Pellicciari, Flavio Moroni, and Domenico E. Pellegrini-Giampietro

Dipartimento di Farmacologia Preclinica e Clinica "Mario Aiazzi Mancini," Università di Firenze, Firenze, Italy (S.A.-T., S.A., F.M., D.E.P.-G.); and Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, Perugia, Italy (M.M., R.P.)

Metabotropic glutamate (mGlu) receptors coupled to phospholipase D (PLD) appear to be distinct from any known mGlu receptor subtype linked to phospholipase C or adenylyl cyclase. The availability of antagonists is necessary for 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 response 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 (IC₅₀ = 70 µM) was noncompetitive in nature and nonselective, because the drug was also able to reduce PLD activation elicited by 100 µM norepinephrine and 1 mM histamine. In the search for a selective and more potent antagonist, 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 [³H]phosphatidylethanol. The (2R,1'S,2'R,3'S)-PCCG stereoisomer (PCCG-13) antagonized the formation of [³H]phosphatidylethanol induced by 100 µM (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in a dose-dependent manner and with a much lower IC₅₀ 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, selective, and competitive antagonist PCCG-13 may represent an important tool for elucidating the role of PLD-coupled mGlu receptors in adult hippocampus.