Synthesis and pharmacological characterization of aminocyclopentanetricarboxylic acids: new tools to discriminate between metabotropic glutamate receptor subtypes.
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 microM), mGluR2 (KB = 88 +/- 21 microM), and mGluR4a (KB = 77 +/- 9 microM), 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 microM) and competitive antagonists with low affinity for mGluR1a and mGluR2 (KB > 300 microM). Finally, (-)-(3R,4R)-ACPT-III [(-)-20] was a competitive antagonist with poor but significant affinity for mGluR4a (KB = 220 microM). 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.
Acher
F C
FC
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, URA 400 CNRS, Université René Descartes-Paris V, France.
Tellier
F J
FJ
Azerad
R
R
Brabet
I N
IN
Fagni
L
L
Pin
J P
JP
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018756:GABA Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection; D014233:Tricarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C108242:1-aminocyclopentane-1,3,4-tricarboxylic acid; D003517:Cyclopentanes; D018755:GABA Agonists; D018756:GABA Antagonists; D007202:Indicators and Reagents; D007295:Inositol Phosphates; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D014233:Tricarboxylic Acids; D007294:Inositol