ABSTRACT
Fluctuations in the endogenous levels of kynurenic acid (KYNA), a potent alpha7 nicotinic and NMDA receptor antagonist, affect extracellular dopamine (DA) concentrations in the rat brain. Moreover, reductions in KYNA levels increase the vulnerability of striatal neurons to NMDA receptor-mediated excitotoxic insults. We now assessed the role of a key KYNA-synthesizing enzyme, kynurenine aminotransferase II (KAT II), in these processes in the rodent striatum, using KAT II KO mice-which have reduced KYNA levels-and the selective KAT II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (S-ESBA) as tools. S-ESBA (applied by reverse dialysis) raised extracellular DA levels in the striatum of KYNA-deficient mice threefold and caused a much larger, 15-fold increase in wild-type mice. In the rat striatum, S-ESBA produced a 35% reduction in extracellular KYNA, which was accompanied by a 270% increase in extracellular DA. The latter effect was abolished by co-infusion of 100 nM KYNA. Intrastriatal S-ESBA pre-treatment augmented the size of a striatal quinolinate lesion by 370%, and this potentiation was prevented by co-infusion of KYNA. In separate animals, acute inhibition of KAT II reduced the de novo synthesis of KYNA during an early excitotoxic insult without enhancing the formation of the related neurotoxic metabolites 3-hydroxykynurenine and quinolinate. Taken together, these results provide further support for the concept that KAT II is a critical determinant of functionally relevant KYNA fluctuations in the rodent striatum.
Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Extracellular Fluid/metabolism , Kynurenic Acid/antagonists & inhibitors , Kynurenic Acid/metabolism , Adenosine/analogs & derivatives , Adenosine/pharmacology , Animals , Animals, Newborn , Corpus Striatum/drug effects , Dose-Response Relationship, Drug , Drug Synergism , Extracellular Fluid/drug effects , Functional Laterality , Kynurenic Acid/pharmacology , Kynurenine/analogs & derivatives , Kynurenine/pharmacology , Mice , Mice, Knockout , Microdialysis/methods , Nerve Degeneration/chemically induced , Nerve Degeneration/pathology , Nerve Degeneration/prevention & control , Norbornanes/pharmacology , Quinolinic Acid/toxicity , Transaminases/deficiency , Tritium/metabolismABSTRACT
Two novel 3'-substituted carboxycylopropylglycines, (2S,1'S,2'S,3'R)-2-(3'-xanthenylmethyl-2'-carboxycyclopropyl)glycine (8a) and (2S,1'S,2'S,3'R)-2-(3'-xanthenylethyl-2'-carboxycyclopropyl)glycine (8b), were synthesized and evaluated as mGluR ligands. Compound 8b showed to be a potent group II antagonist with submicromolar activity.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Glycine/chemical synthesis , Glycine/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Drug Evaluation, Preclinical , Glycine/analogs & derivativesABSTRACT
On the basis of a pharmacophore definition of mGlu4 agonists, the two novel semi-rigid derivatives 12 and 13 were designed and synthesized. The preliminary biological evaluation demonstrated that both compounds interact with hmGlu4a, while ineffective at group II receptor subtypes. In particular, derivative 13 is a full hmGlu4a agonist with an EC50 = 17 microM.
