Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities

In this study, a novel series of imidazole-containing compounds with dual properties, that is, inhibitory potency at the enzyme histamine N-methyltransferase (HMT) and antagonist potency at histamine H-3 receptors was designed and synthesized. Pharmacologically, these new hybrid drugs were evaluated in functional assays for their inhibitory potencies at rat kidney HMT and for their antagonist activities on synaptosomes of rat cerebral cortex. For selected compounds, binding affinities at recombinant human histamine H-3 receptors were determined. The first compounds (1-10) of the series proved to be H-3 receptor ligands of high potency at rat synaptosomes or of high binding affinity at human H-3 receptors, respectively, but of only moderate activity as inhibitors of rat kidney HMT. In contrast, aminoquinoline- or tetrahydroacridine-containing derivatives 11-17 also displayed HMT inhibitory potency in the nanomolar concentration range. Preliminary data from molecular modeling investigations showed that the imidazole derivative 15 and the HMT inhibitor quinacrine possess identical binding areas. The most interesting compound (14) is simultaneously a highly potent H-3 receptor ligand (K-i = 4.1 nM) and a highly potent HMT inhibitor (IC50 = 24 nM), which makes this derivative a valuable pharmacological tool for further development. (C) 2003 Elsevier Science Ltd. All rights reserved.