title: The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D₂ and serotonin 5-HT₁A receptors.
abstract: N-desmethylclozapine (NDMC or norclozapine) is the major active metabolite of the antipsychotic clozapine in humans. The activity of NDMC differs from clozapine at a number of neurotransmitter receptors, probably influencing the pharmacological effects of clozapine treatment. Here, we tested the properties of NDMC in comparison with clozapine at recombinant human dopamine D(2) and serotonin 5-HT(1A) receptors, using a panel of functional assays implicating diverse signalling pathways. At dopamine D(2) receptors, NDMC as well as clozapine did not display agonist activity in measures of G protein activation by [(35)S]GTPγS binding and in the sensitive Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation assay. In contrast, there were weak partial agonist actions of NDMC (but not of clozapine) for dopamine D(2)-dependent activation of Ca(2+) liberation via coexpressed chimeric Gα(q/o) proteins and for G protein-coupled inward rectifier potassium channel (GIRK) current induction in Xenopus oocytes. Intriguingly, GIRK currents induced by NDMC via dopamine D(2) receptors showed a rapid and transient time course, strikingly different from currents recorded with other receptor agonists. At serotonin 5-HT(1A) receptors, NDMC was a more efficacious partial agonist than clozapine for [(35)S]GTPγS binding, ERK1/2 phosphorylation and GIRK activation. Respective low and moderate partial agonist properties of NDMC at dopamine D(2) and serotonin 5-HT(1A) receptors thus differentiate the metabolite from its parent drug and may contribute to the overall effects of clozapine pharmacotherapy.
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, F-81106 Castres Cedex, France. peter.heusler@pierre-fabre.com
authors.forename: Peter
authors.initials: P
authors.lastname: Heusler
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Bruins Slot
authors.forename: Amélie
authors.initials: A
authors.lastname: Tourette
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Tardif
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C058272:norclozapine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003024:Clozapine; D002118:Calcium