DESIGN OF POTENT NON-THIOUREA H-3 RECEPTOR HISTAMINE-ANTAGONISTS

Starting from thioperamide, the first potent and selective H-3-recepto r histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationshi ps. The aim has been to design potent compounds which do not possess t he thiourea group of thioperamide and which may have improved brain pe netration. In a short series of open chain thiourea analogues, the opt imum chain length for H-3-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 thiou rea show H-3-antagonist activity. Furthermore, when the heterocycle is 2-pyridyl, electron-withdrawing substituents (e.g. NO2, CF3, CO(2)Me) in the pyridine 5-position increased potency. The synthesis of 4-[4(5 )-imidazolyl]piperidine and its conversion into the (trifluoromethyl)p yridyl analogue 5b of thioperamide is described; however, 5b is not as potent as thioperamide. Replacing imidazole by pyridine or substituti ng imidazole on the remote N considerably reduced potency. Replacing t he side-chain NH by S increased potency still further and the most pot ent compound is 2-{[2-[4(5)-imidazolyl]ethyl]thio}-5-nitropyrodine (UC L 1199) which has K-i = 4.8 nM.