Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H<sub>3</sub> Receptor Ligands
Mizuki Watanabe,
Takaaki Kobayashi,
Yoshihiko Ito,
Shizuo Yamada,
Satoshi Shuto
Affiliations
Mizuki Watanabe
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060–0812, Japan
Takaaki Kobayashi
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060–0812, Japan
Yoshihiko Ito
Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422–8526, Japan
Shizuo Yamada
Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422–8526, Japan
Satoshi Shuto
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060–0812, Japan
We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.
