Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel

• Published in: Journal of medicinal chemistry 1990-05, Vol.33 (5), p.1296-1305
• Main Authors: Leeson, Paul D, Carling, Robert W, James, Kim, Smith, Julian D, Moore, Kevin W, Wong, Erik H. F, Baker, Raymond
• Format: Article
• Language: English
• Subjects: AMINES; ANIMALS; ANTICONVULSANTS; Anticonvulsants - chemical synthesis; Anticonvulsants - metabolism; Anticonvulsants - pharmacology; AZINES; BASIC BIOLOGICAL SCIENCES; Binding Sites; BIOCHEMICAL REACTION KINETICS; Biological and medical sciences; BODY; BRAIN; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM DEPRESSANTS; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; CHEMICAL BONDS; Dibenzocycloheptenes - metabolism; Dizocilpine Maleate; DRUGS; ELEMENTS; HETEROCYCLIC COMPOUNDS; HYDROGEN; Hydrogen Bonding; HYDROGEN COMPOUNDS; Ion Channels - drug effects; ISOTOPE APPLICATIONS; KINETICS; LIGANDS; MAMMALS; MATHEMATICAL MODELS; Medical sciences; MEMBRANE PROTEINS; Miscellaneous; Models, Molecular; NERVOUS SYSTEM; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; NONMETALS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANS; Pharmacology. Drug treatments; PIPERIDINES; PROTEINS; PYRIDINES; RATS; REACTION KINETICS; RECEPTORS; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; RODENTS; Structure-Activity Relationship; STRUCTURE-ACTIVITY RELATIONSHIPS; TRACER TECHNIQUES; Tritium; TRITIUM COMPOUNDS; VERTEBRATES 550201 > Biochemistry-- Tracer Techniques
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00167a005

Displacement of [3H]MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of the nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo[x.y.z]alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.