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Binding of YM158, a new dual antagonist for leukotriene D4 and thromboxane A2 receptors, to guinea pig lung membranes. 1998

Y Arakida, and K Ohga, and S Kobayashi, and M Yokota, and K Miyata, and T Yamada, and K Honda
Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical, Ibaraki, Japan. arakida.yasuhito@yamanouchi.co.jp

Arachidonic acid metabolites mediate inflammatory responses at a cellular level. The affinity of the newly synthesized compound YM158, 3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesuf onyl)propyl-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate, for leukotriene D4 and thromboxane A2 receptors was examined in radioligand binding assays. YM158 inhibited [3H]leukotriene D4 and [3H]U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha) binding to guinea pig lung membrane preparations, with Ki values of 0.64+/-0.06 nM for leukotriene D4 and 5.0+/-0.88 nM for thromboxane A2 receptors. The Hill coefficients (nH) did not significantly differ from unity, indicating that this antagonism is competitive. In contrast, YM158 showed no affinity for several other receptors, including neurotransmitter-related (alpha1-, alpha2-, beta-adrenoceptors, histamine, 5-HT, muscarinic, sigma), C5a, opioid, Ca2+ channel, K+ channel, protein kinase C, bradykinin, endothelin, neurokinin and platelet activating factor receptors. These studies indicate that YM158 is a highly selective dual antagonist for leukotriene D4 and thromboxane A2 receptors, and this has potential clinical and research applications.

UI MeSH Term Description Entries
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D008297 Male Males
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D011869 Radioligand Assay Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders). Protein-Binding Radioassay,Radioreceptor Assay,Assay, Radioligand,Assay, Radioreceptor,Assays, Radioligand,Assays, Radioreceptor,Protein Binding Radioassay,Protein-Binding Radioassays,Radioassay, Protein-Binding,Radioassays, Protein-Binding,Radioligand Assays,Radioreceptor Assays
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013777 Tetrazoles
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole

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