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