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BM Baron, BW Siegel, BL Harrison, RS Gross, C Hawes and P Towers
Hoechst Marion Roussel, Inc., Cincinnati, Ohio, USA.
MDL 105,519 [(E)-3-(2-phenyl-2-carboxyethenyl)-4, 6-dichloro-1H-indole- 2-carboxylic acid] is a potent ligand at the N-methyl-D-aspartate (NMDA) receptor-associated glycine recognition site and is a noncompetitive inhibitor of NMDA receptor-mediated responses in vitro and in vivo. For purposes of characterizing its action at the glycine binding site, a halogenated analog was reduced with tritium to form radiolabeled MDL 105,519. [3H]MDL 105,519 bound to rat brain membranes with high affinity (Kd = 3.77 nM) and capacity (Bmax = 12.1 pmol/mg protein). Isolation of bound ligand by filtration gave identical levels of specific binding as did centrifugation techniques. The kinetics of the binding reaction were studied. Association was monophasic with Kon equal to 7.0 x 10(7) M-1.min-1. Dissociation was also monophasic with the Koff value calculated from association experiments (0.257 min-1) being similar to that measured directly in dissociation experiments (0.232 min-1). A kinetically derived value for the equilibrium dissociation constant was calculated with the two values for Koff and the association rate constant. The respective values (Kd = 3.67 and 3.31 nM, respectively) agreed well with that obtained from the saturation experiments. The pharmacology of the site labeled by [3H]MDL 105,519 matched that of the glycine recognition site labeled by [3H]glycine. A strong relationship existed between the pKi values of a series of glycine site agonists, partial agonists and antagonists obtained by use of these two radioligands (r = 0.90; P < .0005; slope = 0.997). No effect on specific binding of [3H]MDL 105,519 was observed with ligands (10 microM) interacting with other sites on the NMDA receptor complex or with non-NMDA glutamate recognition sites.
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