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 [I-125]-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 CH3 or electronegative atoms such as an O (as in clozapine-N-oxide); the lack of the CH3 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 CH2, 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.