Synthesis and preliminary pharmacological investigation of new N-substituted-N-[ω-(ω-phenoxy-alkylpiperazin-1-yl)alkyl]guanidines as non-imidazole histamine H3 antagonists

Abstract

Novel, potent non-imidazole histamine H3 receptor antagonists were prepared. Detailed structure-activity studies revealed that N-(4-trifluoromethylbenzyl)-N-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine (pA2 = 8.49 ± 0.05), 1h, and N-(4-nitrobenzyl)-N-[4-(7- phenoxyheptylpiperazin-1-yl)butyl]guanidine (pA2 = 8.43 ± 0.05), 1l, exhibit high affinity for the H3 histamine receptor. The most potent antagonists in this series, 1e, 1h, and 1l, were also in vitro tested as H1 receptor antagonists, showing weak H1-antagonistic activity with pA2 = 6.70 ± 0.09, pA2 = 6.46 ± 0.09, and pA2 = 6.65 ± 0.11, respectively. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA.