title: Distinctive structural requirement for the binding of uncompetitive blockers (phencyclidine-like drugs) to the NMDA receptor.
abstract: The kinetic and equilibrium binding of various tritiated phencyclidine (PCP)-like drugs to the N-methyl-D-aspartate (NMDA) receptor of rat brain cortex were analyzed and compared. The tested drugs showed the following rank order of affinity toward the receptor: [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne maleate ([3H]MK-801) greater than [3H]-N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP greater than [3H]-N[1-(3-aminophenyl)cyclohexyl]piperidine ([3H]NH2PCP) greater than [3H]phencyclidine ([3H]PCP) greater than [3H]-N[1-(3-azidophenyl)cyclohexyl]piperidine ([3H]AZ-PCP) greater than [3H]-N-[1-(3-nitrophenyl)cyclohexyl]piperidine ([3H]NO2PCP) (Kd = 3, 10, 24, 35, 100 and 2500 nM, respectively). All of the labeled ligands were found to associate with and dissociate from the receptor; both processes occurred at relatively slow rates in the absence of added glutamate and its allosteric effector glycine (basal binding) but were markedly accelerated upon their addition. For each drug, the basal association rate was similar to the basal dissociation rate. However, the basal rates differed markedly among the different drugs tested, and their apparent time constants characterizing the first-order process of basal ligand binding (kb) correlated inversely with their equilibrium binding constants (KD). The recorded kb values (10(-3) min-1) were 2.3, 5.1, 12.4, 44 and 79 for [3H]MK-801, [3H]TCP, [3H]NH2PCP, [3H]PCP and [3H]AZ-PCP, respectively. The glutamate- and glycine-induced dissociation rates (characterized by the apparent time constant k-1) differed among the ligands and also correlated inversely with their KD values. Their induced association rates, however, were similar.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Nadler
authors.forename: Y
authors.initials: Y
authors.lastname: Kloog
authors.forename: M
authors.initials: M
authors.lastname: Sokolovsky
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D010622:Phencyclidine; D005998:Glycine