Journal article
New functional activity of aripiprazole revealed: Robust antagonism of D2 dopamine receptor-stimulated Gβγ signaling
Biochemical pharmacology, Vol.93(1), pp.85-91
01/01/2015
DOI: 10.1016/j.bcp.2014.10.014
PMCID: PMC4276521
PMID: 25449598
Abstract
The dopamine D2 receptor (DRD2) is a G protein-coupled receptor (GPCR) that is generally considered to be a primary target in the treatment of schizophrenia. First generation antipsychotic drugs (e.g. haloperidol) are antagonists of the DRD2, while second generation antipsychotic drugs (e.g. olanzapine) antagonize DRD2 and 5HT2A receptors. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, “third generation” antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. Aripiprazole is considered a partial agonist of the DRD2, but it also has partial agonist/antagonist activity for other GPCRs. Further, aripiprazole has been reported to have a unique activity profile in functional assays with the DRD2. In the present study the molecular pharmacology of aripiprazole was further examined in HEK cell models stably expressing the DRD2 and specific isoforms of adenylyl cyclase to assess functional responses of Gα and Gβγ subunits. Additional studies examined the activity of aripiprazole in DRD2-mediated heterologous sensitization of adenylyl cyclase and cell-based dynamic mass redistribution (DMR). Aripiprazole displayed a unique functional profile for modulation of G proteins, being a partial agonist for Gαi/o and a robust antagonist for Gβγ signaling. Additionally, aripiprazole was a weak partial agonist for both heterologous sensitization and dynamic mass redistribution.
Details
- Title: Subtitle
- New functional activity of aripiprazole revealed: Robust antagonism of D2 dopamine receptor-stimulated Gβγ signaling
- Creators
- Tarsis F Brust - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN - 47907, United StatesMichael P Hayes - Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa – 115 S. Grand Ave, Iowa City, IA - 52242, United StatesDavid L Roman - Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa – 115 S. Grand Ave, Iowa City, IA - 52242, United StatesVal J Watts - Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN - 47907, United States
- Resource Type
- Journal article
- Publication Details
- Biochemical pharmacology, Vol.93(1), pp.85-91
- DOI
- 10.1016/j.bcp.2014.10.014
- PMID
- 25449598
- PMCID
- PMC4276521
- NLM abbreviation
- Biochem Pharmacol
- ISSN
- 0006-2952
- eISSN
- 1873-2968
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984065499002771
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