N-Desmethylclozapine

N-Desmethylclozapine is an active metabolite of the atypical antipsychotic clozapine (Item Nos. 12059 | 25779).¹ It was originally described as an antagonist of serotonin (5-HT) receptor subtype 5-HT_2C (IC₅₀ = 7.1 nM in rat choroid plexus) and later as an inverse agonist using human recombinant receptors.^2,3 N-Desmethylclozapine is an antagonist at dopamine D₄ receptors, an agonist at δ-opioid receptors, and a partial agonist at dopamine D₂ and D₃, M₁ muscarinic acetylcholine, and 5-HT_1A receptors.^3,1,4 N-Desmethylclozapine (30 mg/kg) decreases exploratory locomotor activity and increases prepulse inhibition of the acoustic startle response in mice.⁵

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1. Burstein, E.S., Ma, J., Wong, S., et al. Intrinsic efficacy of antipsychotics at human D₂, D₃, and D₄ dopamine receptors: Identification of the clozapine metabolite N-desmethylclozapine as a D₂/D₃ partial agonist. J. Pharmacol. Exp. Ther. 315(3), 1278-1287 (2005).

2. Kuoppamäki, M., Syvälahti, E., and Hietala, J. Clozapine and N-desmethylclozapine are potent 5-HT_1C receptor antagonists. Eur. J. Pharmacol. 245(2), 179-182 (1993).

3. Lameh, J., Burstein, E.S., Taylor, E., et al. Pharmacology of N-desmethylclozapine. Pharmacol. Ther. 115(2), 223-231 (2007).

4. Odagaki, Y., Kinoshita, M., and Ota, T. Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes. J. Psychopharmacol. 30(9), 896-912 (2016).

5. Maehara, S., Hikichi, H., and Ohta, H. Behavioral effects of N-desmethylclozapine on locomotor activity and sensorimotor gating function in mice-Possible involvement of muscarinic receptors. Brain Res. 1418, 111-119 (2011).