title: Novel histamine H3 receptor antagonists: synthesis and evaluation of formamidine and S-methylisothiourea derivatives.
abstract: 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.
authors.affiliation: Research Division, Green Cross Corporation, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Goto
authors.forename: H
authors.initials: H
authors.lastname: Sakashita
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: M
authors.initials: M
authors.lastname: Sugiura
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: C
authors.initials: C
authors.lastname: Fukaya
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis*; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: D000578:Amidines; D006633:Histamine Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D007550:Isothiuronium; C077922:formamidine; C027744:S-methylisothiopseudouronium; C052075:thioperamide