Pharmacological Characterization of 1-Aminoindan-1,5-dicarboxylic Acid, a Potent mGluR1 Antagonist1
- Flavio Moroni1,
- Grazia Lombardi1,
- Christian Thomsen2,
- Patrizia Leonardi1,
- Sabina Attucci1,
- Fiamma Peruginelli1,
- Serenella Albani Torregrossa1,
- Domenico E. Pellegrini-Giampietro1,
- Roberto Luneia3 and
- Roberto Pellicciari3
- 1Dipartimento 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.), 2Health Care Discovery, Novo Nordisk A/S, DK-2760, Mälov, Denmark (C.T.) and 3Istituto di Chimica e Tecnologia del Farmaco, Università di Perugia, 06123 Perugia, Italy (R.L., R.P.)
Abstract
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 (pA 2 = 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 (+)-α-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 (+)-α-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 ofd-[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.
Footnotes
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Send reprint requests to: Prof. Flavio Moroni, Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale Morgagni 65, 50134 Firenze, Italy. E-mail:moronif{at}stat.ds.unifi.it
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↵1 This work was supported by the Italian National Research Council (C.N.R.), the University of Florence and the European Community (Biomed1 Project No. BMH1-CT93–1033 and Biomed2 Project No. BMH4-CT96-0228).
- Abbreviations:
- (1S
- 3R)-ACPD, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid
- AIDA
- (RS)-1-aminoindan-1,5-dicarboxylic acid
- BHK
- baby hamster kidney
- (S)-4C-PG
- (S)-4-carboxyphenylglycine
- IP
- inositol phosphate
- (+)-MCPG
- (+)-α-methyl-4-carboxyphenylglycine
- mGluR
- metabotropic glutamate receptor
- PEt
- phosphatidylethanol
- PLC
- phospholipase C
- PLD
- phospholipase D
- i.c.v.
- intracerebroventricular
- s.c.
- subcutaneous
- i.p.
- intraperitoneal
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- Received September 5, 1996.
- Accepted January 27, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
