Abstract
The present study examined the effects of N-desmethylclozapine (NDMC), a biologically active metabolite of the atypical antipsychotic clozapine, at cloned human opioid receptors stably expressed in Chinese hamster ovary (CHO) cells and at native opioid receptors present in NG108-15 cells and rat brain. In CHO cells expressing the δ-opioid receptor (CHO/DOR), NDMC behaved as a full agonist both in stimulating [35S]GTPγS binding (pEC50=7.24) and in inhibiting cyclic AMP formation (pEC50=6.40). NDMC inhibited [3H]naltrindole binding to CHO/DOR membranes with competition curves that were modulated by guanine nucleotides in an agonist-like manner. Determination of intrinsic efficacies by taking into consideration both the maximal [35S]GTPγS binding stimulation and the extent of receptor occupancy at which half-maximal effect occurred indicated that NDMC had an efficacy value equal to 82% of that of the full δ-opioid receptor agonist DPDPE, whereas clozapine and the other clozapine metabolite clozapine N-oxide displayed much lower levels of agonist efficacy. NDMC exhibited poor agonist activity and lower affinity at the κ-opioid receptor and was inactive at μ-opioid and NOP receptors. In NG108-15 cells, NDMC inhibited cyclic AMP formation and stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 by activating the endogenously expressed δ-opioid receptor. Moreover, in membranes of different brain regions, NDMC stimulated [35S]GTPγS binding and regulated adenylyl cyclase activity and the effects were potently antagonized by naltrindole. These data demonstrate for the first time that NDMC acts as a selective and efficacious δ-opioid receptor agonist and suggest that this unique property may contribute, at least in part, to the clinical actions of the atypical antipsychotic clozapine.
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Acknowledgements
We thank the University of Missouri-Rolla cDNA Resource Center (www.cdna.org) for providing the cDNAs encoding the human opioid receptors.
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Onali, P., Olianas, M. N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors. Neuropsychopharmacol 32, 773–785 (2007). https://doi.org/10.1038/sj.npp.1301152
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DOI: https://doi.org/10.1038/sj.npp.1301152
