Vol. 281, Issue 2, 721-729, 1997

Pharmacological Characterization of 1-Aminoindan-1,5-dicarboxylic Acid, a Potent mGluR1 Antagonist¹

Flavio Moroni, Grazia Lombardi, Christian Thomsen, Patrizia Leonardi, Sabina Attucci, Fiamma Peruginelli, Serenella Albani Torregrossa, Domenico E. Pellegrini-Giampietro, Roberto Luneia and Roberto Pellicciari

Dipartimento di Farmacologia Preclinica e Clinica "Mario Aiazzi Mancini," Università di Firenze, 50134 Firenze, Italy (F.M., G.L., P.L., S.A., F.P., S.A.T., D.E.P.-G.), Health Care Discovery, Novo Nordisk A/S, DK-2760, Mälov, Denmark (C.T.) and Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, 06123 Perugia, Italy (R.L., R.P.)

We examined the pharmacological profile of 1-aminoindan-1,5-dicarboxylic acid (AIDA), a rigid (carboxyphenyl)glycine derivative acting on metabotropic glutamate receptors (mGluRs). In cells transfected with mGluR1a, AIDA competitively antagonized the stimulatory responses of glutamate and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] on phosphoinositide hydrolysis (pA₂ = 4.21). In cells transfected with mGluR5a, AIDA displayed a much weaker antagonist effect. In transfected cells expressing mGluR2, AIDA (1 mM) did not affect the inhibition of forskolin-stimulated adenylate cyclase activity induced by (1S,3R)-ACPD, but at large concentrations, it displayed a modest agonist activity. In rat hippocampal or striatal slices, AIDA (0.1-1 mM) reduced the effects of (1S,3R)-ACPD on phospholipase C but not on adenylate cyclase responses, whereas (+)--methyl-4-carboxyphenylglycine (0.3-1 mM) was an antagonist on both transduction systems. In addition, AIDA (0.3-1 mM) had no effect on mGluRs coupled to phospholipase D, whereas (+)--methyl-4-carboxyphenylglycine (0.5-1 mM) acted as an agonist with low intrinsic activity. In rat cortical slices, AIDA antagonized the stimulatory (mGluR1-mediated) effect of (1S,3R)-ACPD on the depolarization-induced outflow of D-[³H]aspartate, disclosing an inhibitory effect ascribable to (1S,3R)-ACPD activating mGluR2 and/or mGluR4. Finally, mice treated with AIDA (0.1-10 nmol i.c.v.) had an increased pain threshold and difficulties in initiating a normal ambulatory behavior. Taken together, these data suggest that AIDA is a potent, selective and competitive mGluR1a antagonist.