title: Investigation of the bioactive conformation of histamine H3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy.
abstract: We previously identified the highly potent histamine H(3) receptor antagonists (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (1) and its enantiomer ent-1. Although the conformations of 1 and ent-1 are restricted by the central cyclopropane ring, the 2-(4-chlorobenzylamino)ethyl side chain essential for the H(3) receptor binding may somewhat freely rotate. To investigate the bioactive conformation, the 1'-ethyl-substituted derivatives 2a and 2b and their enantiomers ent-2a and ent-2b were designed as side chain conformation-restricted analogues of 1 and ent-1, based on the cyclopropylic strain. These compounds were synthesized, and their analysis by NMR and calculations suggested that the side chain moiety was effectively restricted in a syn-form or an anti-form by the cyclopropylic strain as expected. Pharmacological evaluation and docking simulation showed that the bioactive conformations of 1 and ent-1 appear to be the syn-form and the anti-form, respectively. Thus, the cyclopropylic strain can be effectively used for conformational restriction of the side chain moiety of cyclopropane compounds.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.forename: Naoki
authors.initials: N
authors.lastname: Orimoto
authors.forename: Yasundo
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D003198:Computer Simulation; D003521:Cyclopropanes / Q000737:chemistry*; D054828:Histamine H3 Antagonists / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011485:Protein Binding; D013237:Stereoisomerism
chemical_list: D003521:Cyclopropanes; D054828:Histamine H3 Antagonists; C030797:cyclopropane