title: New functional activity of aripiprazole revealed: Robust antagonism of D2 dopamine receptor-stimulated Gβγ signaling.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN - 47907, United States.
authors.forename: Tarsis F
authors.initials: TF
authors.lastname: Brust
authors.affiliation: Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa - 115 S. Grand Ave, Iowa City, IA - 52242, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hayes
authors.affiliation: Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa - 115 S. Grand Ave, Iowa City, IA - 52242, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Roman
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN - 47907, United States. Electronic address: wattsv@purdue.edu.
authors.forename: Val J
authors.initials: VJ
authors.lastname: Watts
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D004305:Dose-Response Relationship, Drug; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors / Q000502:physiology*; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors / Q000502:physiology*; D057809:HEK293 Cells; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D006220:Haloperidol
keywords: Aripiprazole; Aripiprazole (PubChem CID: 60795); Dopamine; Functional selectivity; GPCR; Gbetagamma; clozapine (PubChem CID: 2818); dopamine hydrochloride (PubChem CID: 65340); haloperidol (PubChem CID: 3559); pramipexole dihydrochloride (PubChem CID: 166589); ropinirole hydrochloride (PubChem CID: 68727); rotigotine hydrochloride (PubChem CID: 180335)