title: Synthesis and structural and pharmacological properties of cyclopropane-based conformationally restricted analogs of 4-methylhistamine as histamine H3/H4 receptor ligands.
abstract: On the basis of the previous results on a histamine H(4) receptor agonist 4-methylhistamine and a cyclopropane-based conformationally restricted analog CEIC (3) with potent H(3)/H(4) receptor antagonistic effect, 4-methylhistamine analogs 4 and 5 of CEIC were designed and synthesized. Compound 4 showed strong affinity (K(i)=38.7 nM) for the H(3) receptor, which was more potent than a well-known H(3) antagonist thioperamide. Stable tautomer and conformation of 3 and 4, which can affect the pharmacological activity, were analyzed by ab initio calculations.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Mizuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.forename: Mika
authors.initials: M
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.forename: Mituhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008761:Methylhistamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; C418607:HRH4 protein, human; D008761:Methylhistamines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; C025566:4-methylhistamine; C030797:cyclopropane