Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H(3)Receptor Ligands

We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H(3)receptor subtype over the H(4)receptor subtype. Notably, compound7showed potent binding affinity and over 100-fold selectivity for the H(3)receptors (K-i= 5.6 nM for H(3)and 602 nM for H-4). 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