Design, synthesis, and in vitro and in vivo characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H3 receptor antagonists

Abstract

Previously, we have shown that 1-substituted-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine with electron withdrawing substituents at position 4 in the benzyl moiety exhibits high in vitro affinities toward the guinea pig jejunal histamine H₃ receptor with pA₂ ranging from 8.49 to 8.43. Here, we present data on the impact of replacement of the piperazine scaffold by the piperidine ring (compounds 2a and 2b), moving benzyl- and 4-trifluoromethylbenzyl substituents from position 1 to 3 of the guanidine moiety (compounds 2c and 2d), which decreases the guanidine basicity (compound 2e), and the influence of individual synthons (compounds 2f–h), present in the lead compounds 1b and 1c, on the antagonistic activity against the histamine H₃ receptor. Additionally, the most active compounds 1a, 1c, and 1d were evaluated for their affinity to the rat histamine H₃ receptor and the human histamine H₃ and H₄ receptors. It was also shown that compounds 1a, 1c and 1d, given parenterally for five days, reduced the food intake of rats and did not influence the brain histamine or noradrenaline concentrations; however, significantly reduced serotonin and dopamine concentrations were found in rats administered with compounds 1a and 1c, respectively.