Differential effect of sodium ions and guanine nucleotides on the binding of thioperamide and clobenpropit to histamine H3-receptors in rat cerebral cortical membranes

Br J Pharmacol. 1995 Jan;114(2):357-62. doi: 10.1111/j.1476-5381.1995.tb13234.x.


1. Conflicting reports in the literature over heterogeneity (West et al., 1990) or homogeneity (Arrange et al., 1990) of histamine H3-receptor binding sites may be attributed to the use of different incubation conditions. In the present study we have investigated the extent to which the binding of H3-receptor ligands to rat cerebral cortical membranes can be modified by both sodium ions and guanine nucleotides. 2. The H3-selective antagonist, thioperamide, discriminated between two specific binding sites for [3H]-N alpha-methylhistamine (IC50 1 = 2.75 +/- 0.87 nM, IC50 2 101.6 +/- 12.0 nM, % site 1 = 24 +/- 2%) in 50 mM Tris HCl buffer, but showed homogeneity of binding in 50 mM Na/K phosphate buffer. 3. Sodium ions markedly altered the binding characteristics of thioperamide (i.e. heterogeneity was lost and IC50 value shifted towards the high affinity site). The competition curves for a second H3-antagonist, clobenpropit and the H3-agonist N alpha-methylhistamine however, were unaltered in the presence of sodium ions. 4. Guanylnucleotides displaced only 60% of specific [3H]-N alpha- methylhistamine binding and modulated thioperamide binding in the same way as sodium ions. 5. These data suggest that the H3-receptor can exist in different conformations for which thioperamide, but not N alpha-methylhistamine and clobenpropit, show differential affinity. 6. The potential nature of these sites, and the implications of this apparent receptor heterogeneity for H3-receptor antagonism by thioperamide, are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Guanine Nucleotides / pharmacology*
  • Histamine Agonists / pharmacology
  • Histamine Antagonists
  • Imidazoles / metabolism*
  • In Vitro Techniques
  • Male
  • Membranes / drug effects
  • Membranes / metabolism
  • Methylhistamines / pharmacology
  • Piperidines / metabolism*
  • Rats
  • Receptors, Histamine H3 / metabolism*
  • Sodium / pharmacology*
  • Thiourea / analogs & derivatives*
  • Thiourea / metabolism


  • Guanine Nucleotides
  • Histamine Agonists
  • Histamine Antagonists
  • Imidazoles
  • Methylhistamines
  • Piperidines
  • Receptors, Histamine H3
  • alpha-methylhistamine
  • Sodium
  • Thiourea
  • thioperamide
  • clobenpropit