BINDING OF CLOZAPINE METABOLITES AND ANALOGS 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 s eries of analogues and metabolites (clozapine-N-oxide, and N-desmethyl clozapine) were tested for their affinity towards the H-3 receptor usi ng the radiolabelled H-3 antagonist [I-125]-iodophenpropit. Qualitativ e structure affinity relationships are derived for the tested compound s. In the clozapine molecule four structurally different moieties may be considered. In comparison with the affinity for the H-3 receptor sh own by clozapine, the following main conclusions can be drawn: The 4-p iperazinyl region does not allow substituents longer than a CH3 or ele ctronegative 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 dr astically alter the affinity for the H-3 receptor, although a basic ni trogen is favoured over CH2, O, or S. The 8 position in ring I is an i mportant modulatory site for H-3 affinity; electronegative substituent s such as chloro and fluoro in this aromatic ring increase the affinit y. When these substituents are: however, present at position X(2) in t he ring, they disable binding to the H-3 receptor. The two major cloza pine metabolites (clozapine-N-oxide, and N-desmethylclozapine) will no t be responsible for a possible contribution of the H-3 receptor antag onism to the clinical profile of clozapine.