Agonist activity of N-Desmethylclozapine, a major clozapine metabolite, at delta opioid receptors.

In the present study we report that N-desmethylclozapine (NDMC), a pharmacologically active metabolite of the atypical antipsychotic clozapine (CLOZ), acts as a selective and efficacious agonist at ð-opioid receptors. In Chinese hamster ovary (CHO) cells stably expressing the human ð-opioid receptor (CHO/DOR), NDMC behaves as a full agonist in stimulating [35S]GTPγS binding and in inhibiting cyclic AMP formation. In radioligand binding assays, NDMC inhibits [3H]naltrindole binding to CHO/DOR membranes with competition curves that are modulated by guanine nucleotides in an agonist-like manner. Estimation of intrinsic efficacies indicates that NDMC has an efficacy value equal to ~ 80% of that of the full ð-opioid receptor agonist DPDPE, whereas CLOZ and the other CLOZ metabolite clozapine N-oxide display a much lower efficacy. NDMC exhibits poor agonist activity at the k-opioid receptor and is inactive at the µ-opioid and NOP receptors. In NG108-15 cells, NDMC inhibits cyclic AMP formation and stimulates ERK1/2 phosphorylation by acting on ð-opioid receptors. Moreover, long-term exposure to NDMC causes desensitization of ð agonist-induced responses. In membranes of different rat brain regions, NDMC stimulates [ 35 S]GTPγS binding and regulates adenylyl cyclase activity and these effects are potently antagonized by naltrindole. These data suggest that the unique property of NDMC to activate ð-opioid receptors may contribute to the clinical actions of the atypical antipsychotic CLOZ.