The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics.
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).
Schlicker
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Institut für Pharmakologie und Toxikologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Marr
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D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines; D001667:Binding, Competitive / Q000187:drug effects; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology*; D003988:Dibenzothiepins / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006633:Histamine Antagonists / Q000378:metabolism*; D007553:Isotope Labeling; D008297:Male; D008761:Methylhistamines / Q000378:metabolism*; D051379:Mice; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D017330:Remoxipride / Q000378:metabolism / Q000494:pharmacology; D018967:Risperidone / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013881:Thioridazine / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D006633:Histamine Antagonists; D008761:Methylhistamines; D018100:Receptors, Histamine H3; D017330:Remoxipride; D014316:Tritium; D001569:Benzodiazepines; D010890:Pirenzepine; C069357:alpha-methylhistamine; D003024:Clozapine; D018967:Risperidone; D013881:Thioridazine; D000077152:Olanzapine; C022172:zotepine