Receptor-specific functional efficacies of alkyl imidazoles as dual histamine H3/H4 receptor ligands

Histamine H₃ and H₄ receptors are highly related G protein-coupled receptors. Preclinical and clinical data strongly suggest the potential therapeutic application of selectively acting histamine H₄ receptor ligands to inflammatory conditions but also hint at a certain interference of the two receptors in diseases attended with itch and pain. The aim of this investigation was to identify dual acting ligands as pharmacological tools. Receptor binding profiles of ω-(1H-imidazol-4-yl)alkyl derivatives structurally defined as amides, carbamates, esters, ethers, ketones and ureas were evaluated with respect to their potencies at histamine H₃ and H₄ receptors. A two-step screening method based on in vitro radioligand binding studies and functional [³⁵S]GTPγS binding experiments was performed. The examined series of imidazole-containing compounds displayed both, selective histamine H₄ receptor and dual acting histamine H₃/H₄ receptor ligands. Slight structural modifications caused major differences in selectivity profiles and on functional properties at the human histamine H₄ receptor. N-(3-(1H-Imidazol-4-yl)propyl)-2-cyclohexylacetamide 11 was identified as most potent and selective human histamine H₄ receptor ligand in this series (K_i = 45 nM). Amide- and ether-containing structures consistently exhibited partial agonist efficacies, whereas ureas, ketones, esters and carbamates mainly acted as antagonists and inverse agonists. We identified novel dual acting histamine H₃/H₄ receptor ligands with varying efficacies at the histamine H₄ receptor subtype, whereas histamine H₃ receptor antagonism was kept constant, e.g. 3-(1H-imidazol-4-yl)propyl (cyclohexylmethyl)carbamate 19 or 4-(3-(3-phenylpropylthio)propyl)-1H-imidazole 30. These compounds state valuable pharmacological tools in studies of diseases, in which histamine H₃ and H₄ receptor signalling contributes to pathophysiological conditions.