Potencies of antagonists chemically related to iodoproxyfan at histamine H3 receptors in mouse brain cortex and guinea-pig ileum: evidence for H3 receptor heterogeneity?

Naunyn Schmiedebergs Arch Pharmacol. 1996 Apr;353(5):482-8. doi: 10.1007/BF00169166.


We determined the affinities of 16 newly synthesized H3 receptor antagonists in an H3 receptor binding assay and the potencies of 12 of these compounds at functional H3 receptors in the mouse brain cortex and guinea-pig ileum. The compounds differ from histamine in that the C-C-N side chain is replaced by a chain of the structure C-C-C-O. The two major aims of the study were (1) to investigate whether the two functional H3 receptors are pharmacologically different and (2) to derive structure-activity relationships. The specific binding of 3H-Na-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the 16 compounds at pKi values ranging from 7.30 to 9.48. In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the electrically evoked tritium overflow was slightly decreased by iodoproxyfan and its deiodo analogue; this effect was counteracted by the H3 receptor antagonist clobenpropit. The other compounds did not affect the evoked tritium overflow by themselves. The concentration-response curve of histamine for its inhibitory effect on the electrically evoked tritium overflow was shifted to the right by the 12 compounds with apparent pA2 values ranging from 7.02 to 9.00. The 12 compounds also shifted to the right the concentration-response curve of R-a-methylhistamine for its inhibitory effect on the electrically induced contraction in guinea-pig ileum strips; the apparent pA2 values ranged from 5.97 to 9.00. Iodoproxyfan decreased the electrically induced contraction by itself and this effect was counteracted by the H3 receptor antagonist thioperamide. The apparent pA2 values in the two functional H3 receptor models showed a highly significant correlation (r = 0.882; P < 0.001). Highly significant correlations were also obtained when the pKi values of the compounds in the binding assay were compared to their apparent pA2 values in the mouse brain (r = 0.799; P < 0.004) and in the guinea-pig ileum (r = 0.851; P < 0.001). In each of the three experimental models, iodoproxyfan was the most potent compound; its deiodo analogue was less potent by more than 1.1 log units. The present results show that the compounds under study possess moderate to high affinity and/or (partial) H3 receptor antagonist potency. The two functional H3 receptors in the mouse brain cortex and the guinea-pig ileum may be slightly different; further studies are necessary to clarify whether this difference is due to H3 receptor heterogeneity, species variants or differences in the efficiency of receptor coupling. The marked difference in the affinity/potency between iodoproxyfan and its deiodo analogue may suggest that a highly lipophilic residue in that part of the molecule favours a high affinity/antagonistic potency at H3 receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Guinea Pigs
  • Histamine Antagonists* / metabolism
  • Histamine Antagonists* / pharmacology
  • Histamine H2 Antagonists / metabolism
  • Histamine H2 Antagonists / pharmacology*
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • In Vitro Techniques
  • Intestine, Small / drug effects*
  • Intestine, Small / metabolism
  • Iodine Radioisotopes
  • Male
  • Methylhistamines / metabolism
  • Mice
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship


  • Histamine Antagonists
  • Histamine H2 Antagonists
  • Imidazoles
  • Iodine Radioisotopes
  • Methylhistamines
  • Piperidines
  • iodoproxyfan
  • thioperamide
  • N-methylhistamine