1 CGS 19755 (cis‐4‐phosphonomethyl‐2‐piperidine carboxylic acid), a rigid analogue of 2‐amino‐5‐phosphonopentanoic acid (AP5), is one of the most potent competitive N‐methyl‐d‐aspartate (NMDA) antagonists described. Using Triton‐treated crude synaptic membranes from rat brain, binding studies indicated that (3H)‐CGS 19755 bound with high affinity and selectivity to the NMDA‐type excitatory amino acid receptor. 2 (3H)‐CGS 19755 binding was saturable, reversible, heat‐labile, pH‐dependent and linear with protein concentration. Specific binding represented 80–85% of the total amount bound. 3 Using a centrifugation assay, saturation experiments revealed two distinct binding components with Kd values of 9 and 200 nM, and corresponding Bmax values of 0.55 and l.00 pmol mg−1 protein. In contrast, a single binding component with a Kd value of 24 nM and an apparent value of 0.74 pmol mg−1 protein was observed with a filtration assay. 4 Competition experiments in which both assay techniques were used, showed that (3H)‐CGS 19755 selectively labels the NMDA receptor. The most active inhibitors of (3H)‐CGS 19755 binding were l‐glutamate and CGS 19755 (IC50 values = 100 nm). 5 In the centrifugation assay, a number of excitatory amino acids were found to generate shallow inhibition curves, and computer analysis indicated the presence of two binding components. The quisqualate receptor ligand AMPA (D,L‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate), kainic acid and the non‐competitive NMDA antagonists, such as phencyclidine, tiletamine and MK‐801, were without activity. 6 The high affinity binding obtained with (3H)‐CGS 19755 by use of filtration techniques thus permits the more rapid evaluation of compounds as potential NMDA antagonists and agonists. Therefore, this rigid analogue of AP5 is a more suitable radioligand for NMDA receptors than (3H)‐CPP (3‐(±)−(2‐carboxypiperazin‐4‐yl)propyl‐l‐phosphonic acid), the corresponding analogue of 2‐amino‐7‐phosphonoheptanoic acid (AP7).
British Journal of Pharmacology – Wiley
Published: Nov 1, 1988
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