Kynurenic acid analogues with improved affinity and selectivity for the glycine site on the N-methyl-D-aspartate receptor from rat brain.

摘要: The glycine site on the N-methyl-D-aspartate (NMDA) subtype of receptors for excitatory neurotransmitter glutamate is a potential target development neuroprotective drugs. We report here two chemical series antagonists derived from kynurenic acid (KYNA), with greatly improved potency and selectivity. Disubstitution chlorine or bromine in 5- 7-positions KYNA increased affinity [3H]glycine binding sites rat cortex/hippocampus P2 membranes, parallel increase antagonism NMDA-evoked responses cortical wedge preparation. optimal compound was 5-I,7-Cl-KYNA, an IC50 29 nM apparent Kb preparation 0.41 microM. Reduction right-hand ring 5,7-diCl-KYNA reduced by 10-fold, but this restored substitution 4-position trans-phenylamide further trans-benzylamide. transphenylurea (L-689,560), 7.4 0.13 Both compounds displayed high degree selectivity site, having values greater than 10 microM versus radioligand to recognition NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate strychnine-sensitive receptor. Selectivity AMPA receptor-mediated also patch-clamp recordings neurons culture. Experiments using [3H]dizocilpine (MK-801) indicated that 5,7-diBr-KYNA, 5,7-diCl-KYNA, L-689,560 all behaved as full were competitive glycine. Patch-clamp culture NMDA-induced currents antagonized competition gave no evidence partial agonist activity. pKi 5,7-diBr-KYNA these experiments 7.2 7.98, respectively, similar affinities assay. new derivatives make them useful tools investigate function NMDA