Binding of Clozapine Metabolites and Analogues to the Histamine H 3 Receptor in Rat Brain Cortex

Following up the finding that the non‐imidazole drug clozapine shows a considerable histamine H 3 receptor antagonistic activity [1,2] , a series of analogues and metabolites (clozapine‐ N ‐oxide, and N ‐desmethylclozapine) were tested for their affinity towards the H 3 receptor using the radiolabelled H 3 antagonist [ 125 I]‐iodophenpropit. Qualitative structure affinity relationships are derived for the tested compounds. In the clozapine molecule four structurally different moieties may be considered. In comparison with the affinity for the H 3 receptor shown by clozapine, the following main conclusions can be drawn: The 4‐piperazinyl region does not allow substituents longer than a CH 3 or electronegative atoms such as an O (as in clozapine‐ N ‐oxide); the lack of the CH 3 group (as in N ‐desmethylclozapine) also reduces the affinity for H 3 receptors. Substitutions at the 5‐diazepine position do not drastically alter the affinity for the H 3 receptor, although a basic nitrogen is favoured over CH 2 , O, or S. The 8 position in ring I is an important modulatory site for H 3 affinity; electronegative substituents such as chloro and fluoro in this aromatic ring increase the affinity. When these substituents are, however, present at position X 2 in the ring, they disable binding to the H 3 receptor. The two major clozapine metabolites (clozapine‐ N ‐oxide, and N ‐desmethylclozapine) will not be responsible for a possible contribution of the H 3 receptor antagonism to the clinical profile of clozapine.