title: Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: Role of 5-HT2Areceptor agonism.
abstract: Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on the concept that SGAs have reduced motor side effects. With this premise, this study examined in HeLa and other cell lines the effects of different APDs on the activation of ERK1/2 (Extracellular signal-regulated kinases) and AKT (Protein Kinase B) kinases, which may be affected in schizophrenia and bipolar disorder. Among the SGAs, Clozapine clearly resulted as the most effective drug inducing ERK1/2 phosphorylation with potency in the low micromolar range. Quetiapine and Olanzapine showed a maximal response of about 50% compared to Clozapine, while FGAs such as Haloperidol and Sulpiride did not have any relevant effect. Among FGAs, Chlorpromazine was able to partially activate ERK1/2 at 30% compared to Clozapine. Referring to AKT activation, Clozapine, Quetiapine and Olanzapine demonstrated a similar efficacy, while FGAs, besides Chlorpromazine, were incapable to obtain any particular biological response. In relation to ERK1/2 activation, we found that 5-HT2Aserotonin receptor antagonists Ketanserin and M100907, both partially reduced Clozapine effect. In addition, we also observed an increase of potency of Clozapine effect in HeLa transfected cells with recombinant 5-HT2Areceptor and in rat glioma C6 cells that express a higher amount of this receptor. This indicates that ERK1/2 stimulation induced by Clozapine could, to some extent, be mediated by 5-HT2Areceptor, through a novel mechanism that is called "biased agonism", even though other cellular targets are involved. This evidence may be relevant to explain the superiority of Clozapine among the APDs.
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Aringhieri
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Kolachalam
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gerace
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Carli
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Verdesca
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Brunacci
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ippolito
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Solini
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy.
authors.forename: Giovanni U
authors.initials: GU
authors.lastname: Corsini
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, Pisa 56126, Italy. Electronic address: marco.scarselli@med.unipi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Scarselli
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003024:Clozapine; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000069348:Quetiapine Fumarate / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D000069348:Quetiapine Fumarate; D012701:Serotonin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003024:Clozapine
keywords: 5-HT(2A); AKT; Antipsychotics; Biased agonism; Clozapine; ERK1/2