A Comparison of [3H]MK-801 and N-[1-(2-Thienyl)cyclohexyl]-3,4-[3H]Piperidine Binding to the N-Methyl-D-Aspartate Receptor Complex in Human Brain

The binding of (+)-3H]5-methyl-10,11-dihydro-5H-dibenzoa,d] cyclohepten-5,10-imine maleate (3H]MK-801) and N-1-(2-thienyl)cyclohexyl]-3,4-3H]piperidine (3H]TCP) to the N-methyl-D-aspartate (NMDA) receptor complex of human brain has been investigated. Significant differences were noted between the binding of the two ligands in the same tissue samples. Binding of both ligands was stimulated by addition of glutamic acid or glycine. However, addition of both compounds resulted in an additional effect with 3H]MK-801 but not 3H]TCP binding. Saturation analysis revealed approximately twice as many high-affinity sites for 3H]MK-801 (Bmax, 1,500 +/- 300 fmol/mg of protein) than for 3H]TCP (Bmax, 660 +/- 170 fmol/mg of protein). In addition, a low-affinity site was detected for 3H]MK-801 binding but not 3H]TCP binding. The pharmacology of the high-affinity 3H]MK-801 and 3H]TCP binding sites was similar with rank order of potency of inhibitors being MK801 greater than TCP greater than phencyclidine greater than N-allylnormetazocine (SKF 10047). 2-Amino-5-phosphonopentanoate inhibited binding of both ligands with comparable potency whereas both 7-chlorokynurenic acid and ZnCl2 were more potent inhibitors of 3H]MK-801 than of 3H]TCP binding. All compounds examined exhibited Hill coefficients of significantly less than unity. Saturation analysis performed in the striatum revealed that the number of binding sites was the same for both 3H]MK-801 (Bmax, 1,403 +/- 394 fmol/mg) and 3H]TCP (Bmax, 1,292 +/- 305 fmol/mg). Addition of glutamate or glycine stimulated striatal binding but there was no further increase on addition of both together.(ABSTRACT TRUNCATED AT 250 WORDS)