Abstract
The four stereoisomers of 1-aminocyclopentane-1,3,4-tricarboxylic acid {ACPT-I (18) and -II (19), (3R,4R)-III [(-)-20], and (3S,4S)-III [(+)-20]} have been synthesized and evaluated for their effects at glutamate receptors subtypes. ACPTs are ACPD analogues in which a third carboxylic group has been added at position 4 in the cyclopentane ring. None of the ACPT isomers showed a significant effect on ionotropic NMDA, KA, and AMPA receptors. On the other hand, ACPT-II (19) was found to be a general competitive antagonist for metabotropic receptors (mGluRs) and exhibited a similar affinity for mGluR1a (KB ) 115 ( 2 íM), mGluR2 (KB ) 88 ( 21 íM), and mGluR4a (KB ) 77 ( 9 íM), the representative members of group I, II and III mGluRs, respectively. Two other isomers, ACPT-I (18) and (+)-(3S,4S)-ACPT-III [(+)-20], were potent agonists at the group III receptor mGluR4a (EC50 ) 7.2 ( 2.3 and 8.8 ( 3.2 íM) and competitive antagonists with low affinity for mGluR1a and mGluR2 (KB > 300 íM). Finally, (-)-(3R,4R)-ACPT-III [(-)-20] was a competitive antagonist with poor but significant affinity for mGluR4a (KB ) 220 íM). These results demonstrate that the addition of a third carboxylic group to ACPD can change its activity (from agonist to antagonist) and either increase or decrease its selectivity and/or affinity for the various mGluR subtypes.