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

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^α-methylhistamine to rat brain cortex homogenates was inhibited by the seven compounds; the pK_i values were: N-desmethyl-clozapine (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 μM), clozapine-N-oxide (3.2–100 μM) and olanzapine (3.2–32 μM). 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 (pK_i 6.15, pA₂ 6.33; Kathmann M, Schlicker E, Göthert M (1994). Psychopharmacology 116: 464–468).