The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine

Abstract

The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

“…In neuronal cells, ERK1/2 is known to participate in molecular pathways regulating learning, memory, and synaptic plasticity (Thomas and Hunganir, 2004). Previously, it has been reported that in mice the systemic administration of NDMC increased phospho-ERK1/2 immunoreactivity in the hippocampus and this response was blocked by pretreatment with scopolamine, indicating the participation of muscarinic receptors (Weiner et al, 2004). Studies in rats have shown that clozapine induced ERK1/2 phosphorylation in prefrontal cortex by blocking serotonin 5HT 2A receptors and that ERK1/2 inhibitors prevented clozapine suppression of the conditioned avoidance response, a behavioral index of antipsychotic activity (Browning et al, 2005).…”

“…Although these values do not allow the determination of the drug concentrations in the biophase, they are comparable with the potencies of NDMC in activating the d-opioid receptor in rat brain membranes. Moreover, whereas clozapine has higher affinity than NDMC at muscarinic M 1 and DA D 2 /D 3 receptors and potently antagonizes NDMC agonist activity at these receptors (Sur et al, 2003;Weiner et al, 2004;Burstein et al, 2005;Li et al, 2005), the affinity of clozapine for the d-opioid receptor is more than 10-fold lower than that of NDMC, suggesting that in the brain the demethylated metabolite could activate the receptors even in the presence of higher concentrations of the parent drug.…”

“…Previous studies have described partial agonist effects of NDMC at the cloned M 1 -M 5 muscarinic receptors (Sur et al, 2003;Weiner et al, 2004;Davies et al, 2005) and D 2 and D 3 DA receptors (Burstein et al, 2005) with potencies generally comparable to those observed in CHO/DOR cells (pEC 50 (Davies et al, 2005) and of 6.94 (Sur et al, 2003) and phosphoinositide hydrolysis with a pEC 50 of 6.7 (Weiner et al, 2004). At D 2 and D 3 DA receptors, NDMC displayed agonist activity equal to 35 and 50% of that of pergolide at the concentration of 20 and 30 nM, respectively (Burstein et al, 2005).…”

“…In the rat brain, concentrations of NDMC higher than those in serum have been detected following clozapine administration, indicating that the metabolite can cross the blood-brain barrier (Weigmann et al, 1999). Moreover, a higher ratio of NDMC to clozapine in plasma was found to correlate positively with clinical improvements, indicating that NDMC may contribute to the clinical efficacy of clozapine (Weiner et al, 2004).…”

“…Thus, in cell lines expressing the cloned human muscarinic receptor subtypes NDMC has been found to act as a partial agonist with potencies and efficacies higher than those of the parent drug (Sur et al, 2003;Weiner et al, 2004;Davies et al, 2005). In CA1 hippocampal neurons, NDMC was found to potentiate NMDA-mediated currents (Sur et al, 2003) and to induce phosphorylation of extracellular signal-regulated kinases (ERK) by activating muscarinic M 1 receptors (Weiner et al, 2004). This receptor has also been shown to mediate the increases in cortical ACh and DA release observed following systemic administration of NDMC in freely moving rats (Li et al, 2005).…”