The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics

Naunyn Schmiedebergs Arch Pharmacol. 1996 Feb;353(3):290-4. doi: 10.1007/BF00168630.

Abstract

We determined the affinity and/or potency of two metabolites of clozapine (clozapine-N-oxide and N-desmethylclozapine) and of five atypical neuroleptics, chemically related (olanzapine) or unrelated to clozapine (remoxipride, risperidone, thioridazine, zotepine), at H3 receptors. The specific binding of 3H-N alpha-methylhistamine to rat brain cortex homogenates was inhibited by the seven compounds; the pKi values were: N-desmethylclozapine (5.33); clozapine-N-oxide (4.18); olanzapine (5.45); thioridazine (4.91); zotepine (4.75); remoxipride (4.51) and risperidone (4.43). Three compounds were examined in a functional H3 receptor model as well. The electrically evoked tritium overflow from superfused mouse brain cortex slices, which represents quasi-physiological noradrenaline release, was not affected by N-desmethylclozapine (3.2 and 10 microM), clozapine-N-oxide (3.2-100 microM) and olanzapine (3.2-32 microM). On the other hand, the three compounds shifted to the right the concentration-response curve of histamine for its inhibitory effect on the evoked overflow; the apparent pA2 values were 5.84, 4.21 and 5.80, respectively. The present study shows that five atypical neuroleptics of different chemical classes and the two major metabolites of clozapine possess a lower affinity and/or antagonistic potency at H3 receptors than clozapine itself (pKi 6.15, pA2 6.33; Kathmann M, Schlicker E, Göthert M (1994). Psychopharmacology 116: 464-468).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / pharmacology*
  • Benzodiazepines
  • Binding, Competitive / drug effects
  • Clozapine / metabolism
  • Clozapine / pharmacology*
  • Dibenzothiepins / metabolism
  • Dibenzothiepins / pharmacology
  • Dose-Response Relationship, Drug
  • Histamine Antagonists / metabolism*
  • Isotope Labeling
  • Male
  • Methylhistamines / metabolism*
  • Mice
  • Olanzapine
  • Pirenzepine / analogs & derivatives
  • Pirenzepine / metabolism
  • Pirenzepine / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Histamine H3 / drug effects
  • Receptors, Histamine H3 / metabolism*
  • Remoxipride / metabolism
  • Remoxipride / pharmacology
  • Risperidone / metabolism
  • Risperidone / pharmacology
  • Structure-Activity Relationship
  • Thioridazine / metabolism
  • Thioridazine / pharmacology
  • Tritium

Substances

  • Antipsychotic Agents
  • Dibenzothiepins
  • Histamine Antagonists
  • Methylhistamines
  • Receptors, Histamine H3
  • Remoxipride
  • Tritium
  • Benzodiazepines
  • Pirenzepine
  • alpha-methylhistamine
  • Clozapine
  • Risperidone
  • Thioridazine
  • Olanzapine
  • zotepine