Design of potent non-thiourea H3-receptor histamine antagonists

J Med Chem. 1995 Aug 18;38(17):3342-50. doi: 10.1021/jm00017a018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects
  • Drug Design
  • Histamine Antagonists* / chemical synthesis
  • Histamine Antagonists* / chemistry
  • Histamine Antagonists* / pharmacology*
  • In Vitro Techniques
  • Rats
  • Synaptosomes / drug effects
  • Thiourea / pharmacology


  • Histamine Antagonists
  • Thiourea