Unexpected partial H1-receptor agonism of imidazole-type histamine H3-receptor antagonists lacking a basic side chain

B. Sadek, S. Elz, H. H. Pertz, H. Stark, W. Schunack

Research output: Contribution to journalArticlepeer-review


Objective and design: The putative partial H1-receptor agonism of some H3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. Methods: Whole segments of guinea-pig ileum were mounted in Tyrode's solution under isotonic conditions in the presence of atropine (10-7 M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H1-receptor agonists were added cumulatively to determine agonist potency (pEC50) and intrinsic activity (Emax) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H1-receptor antagonists were incubated for 3-15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H1 receptor (pKP or pA 2 value, respectively). Results: Several analogues of FUB 372 displayed low H1-receptor affinities (pA2 or pK P 4.2-5.5) except for a methyl benzoate derivative (pA2 = 6.81, Schild plot slope unity). FUB 372, four ortho-substituted derivatives (R = F, CH3, OCH3, CF3), and ciproxifan were weak contractile agents (Emax 9-38%, pEC50 4.73-5.68, histamine: 6.70) susceptible to antagonism by the H1- antihistaminergic drug mepyramine (2·10-9-10-7 M). Agonist potency and H1-receptor affinity of these compounds did not correlate with the data of a set of H1-histaminergic 2-phenylhistamines bearing the same substituents. Conclusions: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H1-receptor agonists lacking a basic side chain.

Original languageEnglish
Pages (from-to)S109-S115
JournalInflammation Research
Issue numberSUPPL. 2
Publication statusPublished - Aug 2004
Externally publishedYes


  • Ciproxifan
  • Guinea-pig ileum
  • Histamine H-receptor agonists
  • Histamine H-receptor antagonists
  • Imoproxifan

ASJC Scopus subject areas

  • Immunology
  • Pharmacology


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