Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors.
Article Details
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Herrick-Davis K, Grinde E, Teitler M
Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors.
J Pharmacol Exp Ther. 2000 Oct;295(1):226-32.
- PubMed ID
- 10991983 [ View in PubMed]
- Abstract
Clozapine is the prototype atypical antipsychotic drug, producing little or no extrapyramidal side effects, while improving negative symptoms of psychosis. Clozapine's high affinity for serotonin receptors has been hypothesized to confer the unique antipsychotic properties of this drug. Recently, we demonstrated that both typical and atypical antipsychotic drugs are inverse agonists at constitutively active 5-hydroxytryptamine2A (5-HT(2A)) receptors. To determine whether inverse agonist activity at 5-HT(2C) receptors plays a role in antipsychotic efficacy, typical and atypical antipsychotic drugs were tested for inhibition of basal inositol phosphate production in mammalian cells expressing rat or human 5-HT(2C) receptors. Atypical antipsychotic drugs (sertindole, clozapine, olanzapine, ziprasidone, risperidone, zotepine, tiospirone, fluperlapine, tenilapine) displayed potent inverse agonist activity at rat and human 5-HT(2C) receptors. Typical antipsychotic drugs (chlorpromazine, loxapine, thioridazine, prochlorperazine, perphenazine, mesoridazine, trifluperidol, fluphenazine, spiperone, haloperidol, pimozide, penfluridol, thiothixene) were devoid of inverse agonist activity, with the exception of loxapine. We review the evidence that loxapine has unique properties characteristic of both atypical and typical antipsychotic drugs. Several typical antipsychotic drugs (chlorpromazine, thioridazine, spiperone, thiothixene) displayed neutral antagonist activity by reversing clozapine inverse agonism. These data suggest that 5-HT(2C) inverse agonist activity is associated with atypical antipsychotic drugs with moderate to high affinity for 5-HT(2C) receptors, and imply that effects of atypical antipsychotic drugs on the 5-HT(2C) receptor may play a role in their unique clinical properties. These data also imply that dysfunction of brain 5-HT(2C) receptor systems may be one of the factors involved in the etiology of psychosis.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Loxapine 5-hydroxytryptamine receptor 2C Protein Humans UnknownAntagonistDetails Mesoridazine 5-hydroxytryptamine receptor 2A Protein Humans YesAntagonistDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Clozapine 5-hydroxytryptamine receptor 2C Ki (nM) 10 N/A N/A Details Fluphenazine 5-hydroxytryptamine receptor 2C Ki (nM) 579 N/A N/A Details Loxapine 5-hydroxytryptamine receptor 2C Ki (nM) 17 N/A N/A Details Olanzapine 5-hydroxytryptamine receptor 2C Ki (nM) 7.8 N/A N/A Details Sertindole 5-hydroxytryptamine receptor 2C Ki (nM) 0.7 N/A N/A Details Ziprasidone 5-hydroxytryptamine receptor 2C Ki (nM) 4.1 N/A N/A Details