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J Pharmacol Exp Ther. 1987 Mar;240(3):778-84.

Binding of [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to rat brain membranes: a selective, high-affinity ligand for N-methyl-D-aspartate receptors.


3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a rigid analog of 2-amino-7-phosphonoheptanoic acid, has been reported as a selective N-methyl-D-aspartate (NMDA) antagonist. [3H]CPP bound with relatively high affinity (Kd = 201 nM) to Triton-treated rat brain crude synaptic membranes using a centrifugation assay. Binding was saturable, reversible, heat sensitive and dependent on protein concentration. Specific binding, which represented 75 to 85% of the total counts bound, was enriched in synaptosomal and microsomal fractions of rat brain, suggesting an involvement in events related to synaptic transmission. On a regional basis, binding was highest in hippocampus, followed by cortex greater than striatum greater than cerebellum = thalamus. No specific binding could be detected in pons medulla or in liver, kidney, heart, lung and adrenal tissue. [3H]CPP binding was stereoselective for the isomers of glutamate, 2-amino-5-phosphonopentanoic acid, homocysteic acid, alpha-aminoadipic acid and N-methyl-aspartate. The most potent compounds tested were L-glutamate and CPP, which were equiactive in displacing [3H]CPP. The order of activity of other excitatory amino acid receptor ligands was D-2-amino-5-phosphonopentanoic acid greater than L-homocysteic acid greater than or equal to DL-2-amino-7-phosphonoheptanoic acid = D-aspartate = L-aspartate greater than L-serine-O-sulfate = D-alpha-aminoadipic acid = ibotenate greater than NMDA greater than DL-2-amino-6-phosphonohexanoic acid greater than quisqualate greater than N-methyl-L-aspartate. The quisqualate- and kainate-type receptor agonists DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and kainic acid, respectively, had negligible activity at 100 microM.(ABSTRACT TRUNCATED AT 250 WORDS).

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