Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic

Tadori, Yoshihiro; Miwa, Takashi; Tottori, Katsura; Burris, Kevin D.; Stark, Arlene; Mori, Toyoki; Kikuchi, Tetsuro

doi:10.1016/j.ejphar.2005.02.051

Cited by 80 publications

(46 citation statements)

References 24 publications

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“…Among the compounds tested, SB-277011 displayed the highest D 3 antagonist selectivity (approximately 100-fold), followed by cariprazine (2.4-fold); however, cariprazine was 27 times more potent at D 3 receptors. Consistent with published data, aripiprazole demonstrated the highest D 2 potency and selectivity (Burris et al, 2002;Shapiro et al, 2003;Tadori et al, 2005Tadori et al, , 2008. Antagonist potencies from the [ In mouse A9 cells expressing human D 2L receptors (cotransfected with Gqo5 protein), dopamine, pramipexole, 7-OH-DPAT, and quinpirole concentration-dependently stimulated IP formation.…”

Section: Discussionsupporting

confidence: 76%

“…Both cariprazine and aripiprazole demonstrated partial agonist activity with relatively low intrinsic efficacy (E max 30 and 34%, respectively) and high or medium potency (pEC 50 8.50 and 7.66, respectively). Potency and efficacy values obtained for aripiprazole were slightly different from those reported earlier (Burris et al, 2002;Tadori et al, 2005); differences were likely caused by dissimilarities in cellular systems and assay methodologies. Our system contains a transfected "promiscuous" Gqo5 protein, which brings about artificial stochiometry and may explain different results obtained with cariprazine and aripiprazole in native tissues.…”

Section: Discussioncontrasting

confidence: 39%

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Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Kiss

Horváth²,

Némethy³

et al. 2010

J Pharmacol Exp Ther

299

310

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receptors and potently antagonized R(ϩ)-2-dipropylamino-7-hydroxy-1,2,3,4-tetra-hydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK b 9.57). In these functional assays, cariprazine showed similar (D 2 ) or higher (D 3 ) antagonist-partial agonist affinity and greater (3-to 10-fold) D 3 versus D 2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D 2 -related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D 3 and D 2 receptors, with very high and preferential affinity to D 3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Dopamine D 3 receptors, cloned in the beginning of the 1990s (Sokoloff et al., 1990), are most abundant in the mesolimbic regions (i.e., nucleus accumbens, island of Calleja) where dysregulation of neurotransmission is thought to be associated with psychosis. The discovery that most antipsychotics, in addition to binding to D 2 receptors, display reasonably high affinity for D 3 receptors, led to the assumption that these receptors may also be responsible for antipsychotic efficacy (Sokoloff et al., 1995). Unfortunately, the selective D 3Article, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 76%

Section: Discussioncontrasting

confidence: 39%

Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Kiss

Horváth²,

Némethy³

et al. 2010

J Pharmacol Exp Ther

299

310

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“…No other D 2 partial agonist has shown similar therapeutic promise to aripiprazole. More importantly, even those who have advocated for simple partial agonism (Burris et al, 2002) now have shown cell-dependent differences in the intrinsic activity of aripiprazole (Tadori et al, 2005). The most parsimonious way to reconcile the available data is accept the hypothesis that the pattern of D 2 functional selectivity, and/or combined with actions at other receptors systems (eg 5-HT 1A , 5-HT 2C , etc), mediate the novel actions of aripiprazole, rather than simple partial agonism.…”

Section: Discussionmentioning

confidence: 99%

Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways

Urban

Vargas

Zastrow

et al. 2006

Neuropsychopharmacol

179

173

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Aripiprazole is a unique atypical antipsychotic drug with an excellent side-effect profile presumed, in part, to be due to lack of typical D 2 dopamine receptor antagonist properties. Whether aripiprazole is a typical D 2 partial agonist, or a functionally selective D 2 ligand, remains controversial (eg D 2 -mediated inhibition of adenylate cyclase is system dependent; aripiprazole antagonizes D 2 receptormediated G-protein-coupled inwardly rectifying potassium channels and guanosine triphosphate nucleotide (GTP)gS coupling). The current study examined the D 2L receptor binding properties of aripiprazole, as well as the effects of the drug on three downstream D 2 receptor-mediated functional effectors: mitogen-activated protein kinase (MAPK) phosphorylation, potentiation of arachidonic acid (AA) release, and D 2 receptor internalization. Unlike quinpirole (a full D 2 agonist) or (À)3PPP (S(À)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, a D 2 partial agonist), the apparent D 2 affinity of aripiprazole was not decreased significantly by GTP. Moreover, full or partial agonists are expected to have Hill slopes o1.0, yet that of aripiprazole was significantly 41.0. Whereas aripiprazole partially activated both the MAPK and AA pathways, its potency vs MAPK phosphorylation was much lower relative to potencies in assays either of AA release or inhibition of cyclic adenosine 3 0 ,5 0 -cyclic monophosphate accumulation. In addition, unlike typical agonists, neither aripiprazole nor (À)3PPP produced significant internalization of the D 2L receptor. These data are clear evidence that aripiprazole affects D 2L -mediated signaling pathways in a differential manner. The results are consistent with the hypothesis that aripiprazole is a functionally selective D 2 ligand rather than a simple partial agonist. Such data may be useful in understanding the novel clinical actions of this drug.

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“…Since the cellular environments are distinct between the NAc and CPu, this theory of functional selectivity may be applied to the present study to explain the regional differences of aripiprazole on PKA signalling. However, the previous evidence was primarily based on in vitro studies (Burris et al, 2002, Kikuchi et al, 1995, Lawler et al, 1999, Mailman and Murthy, 2010, Shapiro et al, 2003, Tadori et al, 2011, Tadori et al, 2007, Tadori et al, 2005, Urban et al, 2007, and the in vivo effects of aripiprazole require further investigation. Moreover, in view that the pathological changes in various mental disorders, the extra-and intra-cellular environments should be different in the patients' brains from those of the normal subjects.…”

Section: Discussionmentioning

confidence: 99%

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

et al. 2016

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The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.

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Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic

Cited by 80 publications

References 24 publications

Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

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Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic

Cited by 80 publications

References 24 publications

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

Contact Info

Product

Resources

About

Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile