[N-Desmethylclozapine is a Selective and Efficacious delta-Opioid Agonist at Recombinant and Native Receptors]
Neuropsychopharmacology. 2006 Jul 12; [Epub ahead of print]
N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious delta-Opioid Agonist at Recombinant and Native Receptors.
Onali P, Olianas MC.
1Department of Neurosciences, Section of Biochemical Pharmacology, University of Cagliari, Cagliari, Italy.
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 delta-opioid receptor (CHO/DOR), NDMC behaved as a full agonist both in stimulating [(35)S]GTPgammaS binding (pEC(50)=7.24) and in inhibiting cyclic AMP formation (pEC(50)=6.40). NDMC inhibited [(3)H]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 [(35)S]GTPgammaS 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 delta-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 kappa-opioid receptor and was inactive at mu-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 delta-opioid receptor. Moreover, in membranes of different brain regions, NDMC stimulated [(35)S]GTPgammaS 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 delta-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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