title: Investigation of the histamine H3 receptor binding site. Design and synthesis of hybrid agonists with a lipophilic side chain.
abstract: As a part of our search for novel histamine H3 receptor agonists, we designed and synthesized hybrid compounds in which the lipophilic (4'-alkylphenylthio)ethyl moiety of a novel H3 receptor agonist, 4-(2-(4'-tert-butylphenylthio)ethyl)-1H-imidazole (1), was incorporated into N(alpha)-methylhistamine, immepip, and immethridine derivatives. These hybrid compounds were expected to interact concurrently with the histamine-binding site and a putative hydrophobic region in the H3 receptor. Among them, piperidine- and pyridine-type derivatives displayed partial agonist activity, and (S)-4-(1-(1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenylthio)ethyl)piperidine (36) was identified as a potent H3 agonist. We performed computational docking studies to examine the binding mode of the agonists. The results indicated that immepip interacts with the key residues, Asp114 and Glu206, in a different manner from histamine. The binding mode of 36 to these residues is similar to that of immepip, and the lipophilic tail of 36 has an additional interaction with a hydrophobic region in transmembrane helix 6 of the receptor. These results indicated that 36 served as a useful tool for studies on receptor-agonist interactions and drug design.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. makoto_ishikawa@meiji.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kudo
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Yokoyama
authors.forename: Miki
authors.initials: M
authors.lastname: Yamauchi
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: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017442:Histamine Agonists; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; D018100:Receptors, Histamine H3