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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-HT2A serotonin 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-HT2A receptor 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-HT2A receptor, 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.
This article was published in the following journal.
Name: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
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A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.
A serotonin receptor subtype found widely distributed in peripheral tissues where it mediates the contractile responses of variety of tissues that contain SMOOTH MUSCLE. Selective 5-HT2A receptor antagonists include KETANSERIN. The 5-HT2A subtype is also located in BASAL GANGLIA and CEREBRAL CORTEX of the BRAIN where it mediates the effects of HALLUCINOGENS such as LSD.
A subtype of dopamine D2 receptors that has high affinity for the antipsychotic CLOZAPINE.
An antipsychotic agent that is structurally related to piperazines and quinolones. It is a partial agonist of SEROTONIN RECEPTOR, 5-HT1A and DOPAMINE D2 RECEPTORS, where it also functions as a post-synaptic antagonist, and an antagonist of SEROTONIN RECEPTOR, 5-HT2A.
An indole derivative effective in schizophrenia and other psychoses and possibly useful in the treatment of the aggressive type of undersocialized conduct disorder. Molindone has much lower affinity for D2 receptors than most antipsychotic agents and has a relatively low affinity for D1 receptors. It has only low to moderate affinity for cholinergic and alpha-adrenergic receptors. Some electrophysiologic data from animals indicate that molindone has certain characteristics that resemble those of CLOZAPINE. (From AMA Drug Evaluations Annual, 1994, p283)