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

Journal Article · Tue May 01 00:00:00 EDT 1990 · Journal of Medicinal Chemistry; (USA)

DOI:https://doi.org/10.1021/jm00167a005· OSTI ID:6810027

Leeson, P D; Carling, R W; James, K; Smith, J D; Moore, K W; Wong, E H; Baker, R ^[1]

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1. Merck Sharp Laboratory, Harlow, Essex (England)

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.

• OSTI ID: 6810027
• Journal Information: Journal of Medicinal Chemistry; (USA), Vol. 33:5; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HYDROGEN
CHEMICAL BONDS
PIPERIDINES
RECEPTORS
ANTICONVULSANTS
BIOCHEMICAL REACTION KINETICS
BRAIN
LIGANDS
MATHEMATICAL MODELS
RATS
STRUCTURE-ACTIVITY RELATIONSHIPS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINES
ANIMALS
AZINES
BODY
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DRUGS
ELEMENTS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NONMETALS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PROTEINS
PYRIDINES
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques