N-Desmethylclozapine (norclozapine, NDMC 13) is one of the two major metabolites of the atypical antipsychotic, clozapine, formed by demethylation by cytochrome P450 enzymes in all species examined, including humans. NDMC is found at serum concentrations comparable to those of clozapine. Like other atypical antipsychotics, NDMC is a weak partial agonist of DA D2 receptors and a potent inverse agonist of 5HT2A receptors. However unlike any other antipsychotic, NDMC is a potent and efficacious muscarinic receptor agonist.23 Specifically, NDMC is a partial agonist of Mi and M5 receptors, and a competitive antagonist of M3 muscarinic receptors. In addition, NDMC was shown to potentiate NMDA receptor currents in CA1 pyramidal cells through an activation of muscarinic receptors,65 and is orally active in several animal models thought to be predictive of antipsychotic activity.

It is possible that the muscarinic agonist properties of NDMC may underlie some of the unique effects of treatment with clozapine. The multiple lines of evidence reported above support a procognitive effect of potentiating central cholinergic neurotransmission, including the clinical effects of acetylcholinesterase inhibitors and direct-acting muscarinic receptor agonists. High-dose clozapine therapy in treatment-refractory schizophrenics may serve to raise brain levels of NDMC to achieve central muscarinic receptor agonist activity, particularly M1 receptor stimulation, rather than recruiting additional lower potency receptor interactions. Given the competing actions at M1 receptors, NDMC/clozapine plasma ratios should be more predictive of therapeutic response, particularly for cognition, than absolute clozapine levels. The NDMC/clozapine ratio is superior to clozapine levels as a predictor of clinical response to clozapine,66 particularly for negative symptoms and cognitive enhancement. Based principally on these data, NDMC is currently being evaluated as a potential stand-alone treatment in patients with schizophrenia.

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