title: Cyclopropane-based stereochemical diversity-oriented conformational restriction strategy: histamine H3 and/or H4 receptor ligands with the 2,3-methanobutane backbone.
abstract: The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins. To develop potent histamine H(3) and/or H(4) receptor ligands, a series of conformationally restricted analogs of histamine with a chiral trans- or cis-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane structure was designed based on this strategy. These stereochemically diverse compounds were synthesized from previously developed versatile chiral cyclopropane units. Among these analogs, a trans-cyclopropane-type compound, (2S,3R)-4-(4-chlorobenzylamino)-2,3-methano-1-(1H-imidazol-4-yl)butane (5b), has remarkable antagonistic activity to both the H(3) (K(i) = 4.4 nM) and H(4) (K(i) = 5.5 nM) receptors, and a cis-cyclopropane-type compound, (2R,3R)-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane (6a), is a potent and selective H(3) receptor partial agonist (K(i) = 5.4 nM). Although (2S,3R)-4-amino-2,3-methano-1-(1H-imidazol-4-yl)butane (5a) does not have a hydrophobic group which the usual H(3) receptor antagonists have, it was found to be a potent H(3) receptor antagonist (K(i) = 20.1 nM). Thus, a variety of compounds with different pharmacological properties depending on the cyclopropane backbones and also on the side-chain functional groups were identified. In addition to the previously used 1,2-methanobutane backbone, the 2,3-methanobutane backbone also worked effectively as a cyclopropane-based conformational restriction structure. Therefore, the combination of these two cyclopropane backbones increases the stereochemical and three-dimensional diversity of compounds in this strategy, which can provide a variety of useful compounds with different pharmacological properties.
authors: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan.
authors: Mizuki
authors: M
authors: Watanabe
authors: Takaaki
authors: T
authors: Kobayashi
authors: Takatsugu
authors: T
authors: Hirokawa
authors: Akira
authors: A
authors: Yoshida
authors: Yoshihiko
authors: Y
authors: Ito
authors: Shizuo
authors: S
authors: Yamada
authors: Naoki
authors: N
authors: Orimoto
authors: Yasundo
authors: Y
authors: Yamasaki
authors: Mitsuhiro
authors: M
authors: Arisawa
authors: Satoshi
authors: S
authors: Shuto
mesh_terms: D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology*; D006632:Histamine / Q000031:analogs & derivatives; D017442:Histamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013237:Stereoisomerism
chemical_list: D003521:Cyclopropanes; C418607:HRH4 protein, human; D017442:Histamine Agonists; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D006632:Histamine