Histamine H(3) and H(4) receptors are highly related G protein-coupled receptors. Preclinical and clinical data strongly suggest the potential therapeutic application of selectively acting histamine H(4) 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 H(3) and H(4) receptors. A two-step screening method based on in vitro radioligand binding studies and functional [(35)S]GTPγS binding experiments was performed. The examined series of imidazole-containing compounds displayed both, selective histamine H(4) receptor and dual acting histamine H(3)/H(4) receptor ligands. Slight structural modifications caused major differences in selectivity profiles and on functional properties at the human histamine H(4) receptor. N-(3-(1H-Imidazol-4-yl)propyl)-2-cyclohexylacetamide 11 was identified as most potent and selective human histamine H(4) receptor ligand in this series (K(i)=45nM). 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 H(3)/H(4) receptor ligands with varying efficacies at the histamine H(4) receptor subtype, whereas histamine H(3) 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 H(3) and H(4) receptor signalling contributes to pathophysiological conditions.
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