No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation

Abstract

The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.

Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo

“…The nanomolar antagonist potency of clozapine at human H 1 Rs is consistent with its binding affinity (Bymaster et al 1996;Kroeze et al 2003;Lameh et al 2007;Nasrallah 2008;Richelson and Nelson 1984;Richelson and Souder 2000;Schotte et al 1996;Theisen et al 2007). A 30-fold-higher antagonist potency has been reported, but it likely resulted from the cell-based assay used, inasmuch as clozapine was 20-50-fold more potent as antagonist than NDMC (Lameh et al 2007;Weiner et al 2004), whereas both compounds displayed here the same nanomolar antagonist potency.…”

Paranoid Schizophrenia is Characterized by Increased CB1 Receptor Binding in the Dorsolateral Prefrontal Cortex

“…First, we found no correlation between lifetime antipsychotic drug exposure and CB 1 R density or mRNA expression. Second, the existing body of evidence suggests overall that most antipsychotic drugs do not bind the CB 1 R in vitro (Theisen et al, 2007). In rats, antipsychotics do not change the CB 1 R binding in the cortex and striatum (the regions with some of the highest density of CB 1 R) (Sundram et al, 2005;Wiley et al, 2008) but may decrease the CB 1 R in the brainstem and nucleus accumbens (Sundram et al, 2005;Weston-Green et al, 2008), or, in the case of risperidone, may increase CB 1 R binding in the hypothalamus, hippocampus, and amygdala (Secher et al, 2010).…”

Short-term treatment with olanzapine does not modulate gut hormone secretion: olanzapine disintegrating versus standard tablets

“…In rodents, olanzapine reduced PYY-binding densities in different parts of the brain (32), indicating that the drug might indeed counteract the central effects of PYY. In a recent study, olanzapine exhibited a negligible affinity for a number of anorexigenic neuroreceptors, including those of CCK (40). Unfortunately, the drug's affinity for GLP-1, PYY, and OXM receptors was not studied.…”