Clozapine-d4 is intended for use as an internal standard for the quantification of clozapine by GC- or LC-MS. Clozapine is a partial agonist at the serotonin (5-HT) receptor subtype 5-HT1A (Ki = 180 nM).1,2 It also binds to 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 receptors (Kis = 3.3, 13, 110, 4, and 21 nM, respectively), as well as the histamine H1 and α1-adrenergic receptors (Kis = 2.1 and 23 nM, respectively). It does not bind to the 5-HT1B receptor and has a lower affinity for dopamine receptors (Kis = 540, 150, and 360 nM for D1-3, respectively). Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters.3 It reverses locomotor hyperactivity and deficits in prepulse inhibition of acoustic startle in a rat neonatal ventral hippocampal ibotenic lesion model of schizophrenia when administered at a dose of 2.5 mg/kg per day.4 Formulations containing clozapine have been used in the treatment of schizophrenia.
1.Millan, M.J.Improving the treatment of Schizophrenia: Focus on serotonin (5-HT)1A receptorsJ. Pharmacol. Exp. Ther.295(3)853-861(2000) 2.Schotte, A., Janssen, P.F., Gommeren, W., et al.Risperidone compared with new and reference antipsychotic drugs: In vitro and in vivo receptor bindingPsychopharmacology (Berl)124(1-2)57-73(1996) 3.Tanahashi, S., Yamamura, S., Nakagawa, M., et al.Clozapine, but not haloperidol, enhances glial D-serin and L-glutamate release in rat frontal cortex and primary cultured astrocytesBr. J. Pharmacol.1651543-1555(2012) 4.Rueter, L.E., Ballard, M.E., Gallagher, K.B., et al.Chronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophreniaPsychopharmacology (Berl).176(3-4)312-319(2004)