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Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms
- Source :
- Biochemical pharmacology. 71(4)
- Publication Year :
- 2005
-
Abstract
- In this study we have functionally characterized aripiprazole (OPC-14597; 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy-3,4-dihydro-2-(1H)-quinolinone), the prototype of a new generation antipsychotic drug termed dopamine-serotonin-system stabilizer, in cells expressing 5-hydroxytryptamine2 (5-HT2) receptor subtypes in comparison with olanzapine. In Chinese hamster ovary (CHO) cells stably expressing 5-HT2 receptors, aripiprazole displayed a dual agonist/antagonist profile for 5-HT2C receptor (VNI isoform) mediated calcium signaling (EC50 1070 nM, IC50 281 nM). It exhibited no appreciable 5-HT2A or 5-HT2B agonism, whereas it antagonized 5-HT-stimulated calcium increase at either 5-HT2A or 5-HT2B receptor expressed in CHO cells (IC50s of 369 and 0.46 nM, respectively). In comparison, olanzapine was devoid of agonism but was an antagonist at all three subtypes, with a potency rank order of 5-HT2A (IC50, 2.5 nM)>5-HT2B (47 nM)>5-HT2C (69 nM). In human embryonic kidney (HEK) cells transiently expressing 5-HT2C receptor isoforms, aripiprazole exhibited full agonism at the unedited INI, but partial agonism at the partially edited VNI and fully edited VSV isoforms (EC50s of 571, 1086 and 2099 nM, respectively). A partial antagonism was also observed for aripiprazole at the two edited isoforms (IC50s of 1138 and 1000 nM, respectively). In contrast, while lacking agonist activity at the VNI and VSV, olanzapine showed inverse agonism at the INI isoform (IC50 594 nM), reaching a maximal attenuation of 20%. In addition, olanzapine was a full antagonist at all three isoforms, with a rank order of potency of VNI (IC50, 79 nM)>VSV (101 nM)>INI (3856 nM). The modest 5-HT2A antagonism and 5-HT2C partial agonism, along with reported D2 and 5-HT1A partial agonism, may allow aripiprazole to stabilize the disturbed dopamine-serotonin interplay in schizophrenia with a moderate yet adequate pharmacological intervention. 5-HT2C agonism may also underlie the minimal weight gain seen with aripiprazole.
- Subjects :
- Agonist
medicine.medical_specialty
medicine.drug_class
Aripiprazole
Intracellular Space
Atypical antipsychotic
CHO Cells
Pharmacology
Quinolones
Transfection
Biochemistry
Partial agonist
Piperazines
Cell Line
Benzodiazepines
Cricetulus
Internal medicine
Cricetinae
medicine
Receptor, Serotonin, 5-HT2C
Animals
Humans
Protein Isoforms
Receptor
Dose-Response Relationship, Drug
Chemistry
HEK 293 cells
Antagonist
5-HT2C receptor
Endocrinology
Olanzapine
Serotonin 5-HT2 Receptor Antagonists
Calcium
Female
RNA Editing
Selective Serotonin Reuptake Inhibitors
medicine.drug
Antipsychotic Agents
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 71
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Biochemical pharmacology
- Accession number :
- edsair.doi.dedup.....a1018d1202bd2468b08ac09dcc420d1d