Novel histamine H3 receptor antagonists: synthesis and evaluation of formamidine and S-methylisothiourea derivatives

In order to obtain a new, potent and selective histamine H3 receptor antagonists, chemical modifications of thioperamide, a well-known H3 receptor antagonist, were conducted. A new series of compounds has been synthesized by modifying the thiourea and cyclohexyl groups of thioperamide, and tested for H3 affinity by receptor binding assay using plasma membrane from rat cerebral cortex. The thiourea group of thioperamide was found to be replaceable with a basic moiety such as formamidine or S-methylisothiourea. Replacement of the cyclohexyl group in thioperamide by a 1-adamantyl or an exo-2-norbornyl group increased the affinity for H3 receptor. Among the compounds synthesized, N-(1-adamantyl)-N',N'-[3-(4(5)-1H-imidazolyl)pentamethylene] formamidine 3f (AQ0145) showed the highest H3 receptor affinity, having a potent antagonistic activity. This compound was at least 1,000-fold more active towards H3 than towards H1 and H2 receptors.