PHARMACOLOGICAL CHARACTERIZATION OF 1-AMINOINDAN-1,5-DICARBOXYLIC ACID, A POTENT MGLUR1 ANTAGONIST

We examined the pharmacological profile of 1-aminoindan-1,5-dicarboxyl ic acid (AIDA), a rigid (carboxyphenyl)glycine derivative acting on me tabotropic glutamate receptors (mGluRs). In cells transfected with mGl uR1a, AIDA competitively antagonized the stimulatory responses of glut amate and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-A CPD] on phosphoinositide hydrolysis (pA(2) = 4.21). In cells transfect ed with mGluR5a, AIDA displayed a much weaker antagonist effect. In tr ansfected cells expressing mGluR2, AIDA (less than or equal to 1 mM) d id not affect the inhibition of forskolin-stimulated adenylate cyclase activity induced by (IS,3R)-ACPD, but at large concentrations, it dis played a modest agonist activity. In rat hippocampal or striatal slice s, AIDA (0.1-1 mM) reduced the effects of(1S,3R)-ACPD on phospholipase C but not on adenylate cyclase responses, whereas (+)-alpha-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 (+)-alpha-methyl-4-carboxyphenylglycine ( 0.5-1 mM) acted as an agonist with low intrinsic activity. In rat cort ical slices, AIDA antagonized the stimulatory (mGluR1-mediated) effect of (1S,3R)-ACPD on the depolarization-induced outflow of D-[H-3]aspar tate, disclosing an inhibitory effect ascribable to (1S,3R)-ACPD activ ating mGluR2 and/or mGluR4 Finally, mice treated with AIDA (0.1-10 nmo l i.c.v.) had an increased pain threshold and difficulties in initiati ng a normal ambulatory behavior. Taken together, these data suggest th at AIDA is a potent, selective and competitive mGluR1a antagonist.