title: Design of potent non-thiourea H3-receptor histamine antagonists.
abstract: Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design potent compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. In a short series of open chain thiourea analogues, the optimum chain length for H3-antagonist potency was found to be (CH2)3. Compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side chain amino group in place of thiourea show H3-antagonist activity. Furthermore, when the heterocycle is 2-pyridyl, electron-withdrawing substituents (e.g. NO2, CF3, CO2Me) in the pyridine 5-position increased potency. The synthesis of 4-[4(5)-imidazolyl]piperidine and its conversion into the (trifluoromethyl)pyridyl analogue 5b of thioperamide is described; however, 5b is not as potent as thioperamide. Replacing imidazole by pyridine or substituting imidazole on the remote N considerably reduced potency. Replacing the side-chain NH by S increased potency still further and the most potent compound is 2-([2-[4(5)-imidazolyl]ethyl]thio)-5-nitropyridine (UCL 1199) which has Ki = 4.8 nM.
authors.affiliation: Department of Chemistry, Christopher Ingold Laboratories, University College London, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: S K
authors.initials: SK
authors.lastname: Hosseini
authors.forename: Y S
authors.initials: YS
authors.lastname: Khalaf
authors.forename: W
authors.initials: W
authors.lastname: Tertiuk
authors.forename: J M
authors.initials: JM
authors.lastname: Arrang
authors.forename: M
authors.initials: M
authors.lastname: Garbarg
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects; D013890:Thiourea / Q000494:pharmacology
chemical_list: D006633:Histamine Antagonists; D013890:Thiourea