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

  title={Aripiprazole has Functionally Selective Actions at Dopamine D2 Receptor-Mediated Signaling Pathways},
  author={Jonathan D. Urban and Gabriel A. Vargas and Mark Zastrow and Richard B. Mailman},
Aripiprazole is a unique atypical antipsychotic drug with an excellent side-effect profile presumed, in part, to be due to lack of typical D2 dopamine receptor antagonist properties. Whether aripiprazole is a typical D2 partial agonist, or a functionally selective D2 ligand, remains controversial (eg D2-mediated inhibition of adenylate cyclase is system dependent; aripiprazole antagonizes D2 receptor-mediated G-protein-coupled inwardly rectifying potassium channels and guanosine triphosphate… 

D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.

This work discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the Gi/o pathway over β-arrestin2 as a structure-functional selectivity relationship study and showed selective agonist activity for D2R over D3R.

Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo shows that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors, consistent with the hypothesis that aripIPrazole is a functionally selective D2R ligand.

Antagonism of dopamine D2 receptor/β-arrestin 2 interaction is a common property of clinically effective antipsychotics

It is demonstrated that while different classes of antipsychotics have complex pharmacological profiles at G protein-dependent D2R long isoform (D2LR) signaling, they share the common property of antagonizing dopamine-mediated interaction of D2LR with β-arrestin 2.

Pharmacological blockade of dopamine D2 receptors by aripiprazole is not associated with striatal sensitization

The putative involvement of other pharmacological targets for aripiprazole that would support in the prevention of secondary effects commonly associated with the blockade of striatal dopamine D2 receptors are highlighted.

Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3β Signalling Pathways in Rats

It is suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas.

Discovery of β-Arrestin–Biased Dopamine D2 Ligands for Probing Signal Transduction Pathways Essential for Antipsychotic Efficacy

The results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects.



Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D2 Receptors

These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer.

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

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

The results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of ‘functionally selective’ activation of D2 (and possibly D3)-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors—particularly 5-HT receptor subtypes (5-HT1A, 5- HT2A).

Dopamine activation of the arachidonic acid cascade as a basis for D1D2 receptor synergism

In Chinese hamster ovary cells transfected with the D2 receptor complementary DNA, D2 agonists potently enhance arachidonic acid release, provided that such release has been initiated by stimulating constitutive purinergic receptors or by increasing intracellular Ca2+.

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase.

The hypothesis that DHX causes agonist-typical functional changes only at some of these receptors, termed "functional selectivity", suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery.

Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus.

Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy.

Differential Regulation of the Dopamine D2and D3 Receptors by G Protein-coupled Receptor Kinases and β-Arrestins*

Functional distinctions between the D2R and D3R may be found in their desensitization and cellular trafficking properties, and the differences in their regulatory properties suggest that they have distinct physiological roles in the brain.

Novel Mechanisms of Drug Action: Functional Selectivity at D2 Dopamine Receptors

This chapter will demonstrate the phenomenon with the dopamine D 2 receptor, and show how both model compounds and the novel atypical antipsychotic drug aripiprazole have function-specific characteristics, and provide two examples showing that functional selectivity in vitro predicts novel behavioral effects in vivo.

Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs.

The current study explores the underlying mechanism using transfected MN9D cells and D(2)-producing anterior pituitary lactotrophs to provide compelling evidence for agonist-induced functional selectivity with the D( 2L) receptor.