title: Unique binding pocket for KW-4679 in the histamine H1 receptor.
abstract: The histamine H1 receptor has an aspartate (Asp) residue in transmembrane helix 3 (TM3), which is well-conserved among biogenic amine receptors. The Asp residue is one of the most crucial amino acids for ligand binding. The tested histamine H1 receptor antagonists with tri- and tetracyclic structures were not selective for histamine H1 receptors and showed affinity for several other biogenic amine receptors. In contrast, KW-4679 ((Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b, e]oxepin-2-acetic acid hydrochloride), a tricyclic compound, was a selective histamine H1 receptor antagonist. [3H]KW-4679 had high affinity (Kd value of 2.5 +/- 0.12 nM) for wild-type human histamine H1 receptors. In the [3H]KW-4679 binding assay, replacement of Asp107 by alanine by site-directed mutagenesis greatly reduced the affinities (280-2100-fold) of tri- and tetracyclic compounds, whereas this mutation led to a comparatively small reduction (14-fold) in KW-4679 affinity. These results demonstrate that the tested tri- and tetracyclic histamine H1 receptor antagonists which have a tight interaction with the Asp residue are not selective for the histamine H1 receptor. Furthermore, the high selectivity of KW-4679 might be explained by a unique binding pocket, which consists of the Asp residue and other acceptor sites, in the histamine H1 receptor.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo, Sunto, Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nonaka
authors.forename: S
authors.initials: S
authors.lastname: Otaki
authors.forename: E
authors.initials: E
authors.lastname: Ohshima
authors.forename: M
authors.initials: M
authors.lastname: Kono
authors.forename: H
authors.initials: H
authors.lastname: Kase
authors.forename: K
authors.initials: K
authors.lastname: Ohta
authors.forename: H
authors.initials: H
authors.lastname: Fukui
authors.forename: M
authors.initials: M
authors.lastname: Ichimura
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003990:Dibenzoxepins / Q000378:metabolism*; D017442:Histamine Agonists / Q000378:metabolism / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D000069605:Olopatadine Hydrochloride; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D003990:Dibenzoxepins; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D000069605:Olopatadine Hydrochloride