Protein binding properties of some histamine H2 antagonists: a 1H nuclear magnetic resonance study of antihistamine-calmodulin interactions.
Oxmetidine (SK & F 92994) is a potent histamine H2 antagonist, which, however, also demonstrates cardiac effects consistent with its inhibiting transmembrane calcium fluxes. 1H nuclear magnetic resonance has been used to show that oxmetidine binds to a single site on the regulatory calcium-binding protein, calmodulin. Binding requires the presence of at least two equivalents of calcium per mol protein, is characterized by fast exchange behaviour and a dissociation constant of about 4 mM and is not affected by the presence of trifluoperazine. Protein-induced spectral changes and a limited study of structure-affinity relationships suggest the importance of the drug imidazole and benzyldioxymethylene groups in determining the strength of the interaction. Drug-induced perturbations in the spectrum of calmodulin indicate that the binding site is in the C-terminal half of the protein, and involves a hydrophobic area containing His-107, Met-144, Met-145 and possibly Phe-89, Phe-141, and calcium binding site III.
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D000818:Animals; D001921:Brain / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002417:Cattle; D003903:Deuterium; D017666:Deuterium Oxide; D006635:Histamine H2 Antagonists / Q000378:metabolism*; D006859:Hydrogen; D007093:Imidazoles / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011485:Protein Binding; D014867:Water
D002147:Calmodulin; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D014867:Water; D006859:Hydrogen; D003903:Deuterium; D017666:Deuterium Oxide; C027703:oxmetidine