Binding of Clozapine Metabolites and Analogues to the Histamine H₃ Receptor in Rat Brain Cortex

Abstract

Following up the finding that the non-imidazole drug clozapine shows a considerable histamine H3 receptor antagonistic activity, a series of analogues and metabolites (clozapine-N-oxide, and N-desmethylclozapine) were tested for their affinity towards the H3 receptor using the radiolabelled H3 antagonist [125I]-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 H3 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 H3 receptors. Substitutions at the 5-diazepine position do not drastically alter the affinity for the H3 receptor, although a basic nitrogen is favoured over CH2, O, or S. The 8 position in ring I is an important modulatory site for H3 affinity; electronegative substituents such as chloro and fluoro in this aromatic ring increase the affinity. When these substituents are, however, present at position X2 in the ring, they disable binding to the H3 receptor. The two major clozapine metabolites (clozapine-N-oxide, and N-desmethylclozapine) will not be responsible for a possible contribution of the H3 receptor antagonism to the clinical profile of clozapine.

Activation of endogenous arginine vasopressin neurons inhibit food intake: by using a novel transgenic rat line with DREADDs system

“…We should try another dosage to clarify the effects of CNO on AVP neurons by further study, however, there are some issues to be noticed. Although, CNO is thought to be largely an inactive metabolite 20,21 , some studies reported that administration of CNO caused detectable levels of clozapine which was retro-converted from CNO in the plasma of humans and guinea pigs 22,23 , which may affect animals behavior. Thus, we should pay close attention to the dosage of CNO when conducting behavioural experiments by using DREADDs system.…”

Altered histamine H3 receptor radioligand binding in post‐mortem brain samples from subjects with psychiatric diseases

“…, 1995; Rodrigues et al. , 1995; Alves‐Rodrigues et al. , 1996), subjects who were treated with any of the ATAs or TCAs were included into the ‘ATA/TCA’ groups, while subjects who were treated with typical antipsychotics, mood stabilizers or non‐TCA antidepressants were included in the ‘other medication’ groups.…”

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

“…While clozapine is known to bind to many receptors (Coward, 1992; Schotte et al, 1993; Peters, 2012), the few studies that investigated the pharmacological actions of CNO failed to find any effects. This has led to the consensus that CNO is largely an inactive metabolite (Alves-Rodrigues et al, 1996; Salmi and Ahlenius, 1996; Wong et al, 1996). However, administration of CNO leads to detectable levels of clozapine in the plasma of humans and guinea pigs (Jann et al, 1994; Chang et al, 1998).…”