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

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Abstract
The binding of (+)‐[3H]5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,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 > TCP > phencyclidine > 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. It is concluded either that MK801 and TCP do not interact with NMDA receptors in an identical manner, or that NMDA receptors in human cortical membranes are heterogeneous.