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, compound 7 showed 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.