New high affinity H3 receptor agonists without a basic side chain

Ruengwit Kitbunnadaj, Marcel Hoffmann, Silvina A. Fratantoni, Gerold Bongers, Remko A. Bakker, Kerstin Wieland, Ahmed El Jilali, Iwan J.P. De Esch, Wiro M.P.B. Menge, Henk Timmerman, Rob Leurs

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.

Original languageEnglish
Pages (from-to)6309-6323
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number23
DOIs
StatePublished - 1 Dec 2005
Externally publishedYes

Keywords

  • Agonists
  • Histamine H receptor
  • Selective

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