title: Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice.
abstract: The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound, 4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain N(tau)-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident-intruder test.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Rie
authors.initials: R
authors.lastname: Shinei
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Yokoyama
authors.forename: Miki
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Masayo
authors.initials: M
authors.lastname: Oyama
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Okuma
authors.forename: Takako
authors.initials: T
authors.lastname: Nagayama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kato
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Kakui
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sato
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001923:Brain Chemistry; D006632:Histamine / Q000031:analogs & derivatives* / Q000737:chemistry; D017442:Histamine Agonists / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D057927:Hydrophobic and Hydrophilic Interactions; D008761:Methylhistamines / Q000032:analysis; D051379:Mice; D011968:Receptors, Histamine / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: D017442:Histamine Agonists; D008761:Methylhistamines; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D006632:Histamine