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

Article abstract of DOI:10.1248/cpb.45.305

In order to obtain a new, potent and selective histamine, H₃ receptor antagonist, 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 receptor 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 1000-fold more active towards H₃ than towards H₁ and H₂ receptors.

Full text of DOI:10.1248/cpb.45.305

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NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service