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The antipsychotic aripiprazole is a non‐competitive antagonist of dopamine‐stimulated D 2 receptor interactions with β‐arrestin‐2
Author(s) -
Free R Benjamin,
Dalefield Martin,
Miller Brittney N,
Doyle Trevor B,
Conroy Jennie L,
Vangveravong Suwanna,
Duan Lihua,
Javitch Jonathan A,
Mach Robert H,
Sibley David R
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.665.2
Subject(s) - aripiprazole , partial agonist , agonist , pharmacology , chemistry , arrestin , dopamine receptor d2 , antipsychotic , receptor , dopamine , mechanism of action , competitive antagonist , antagonist , intrinsic activity , dopamine receptor , medicine , schizophrenia (object oriented programming) , g protein coupled receptor , psychology , biochemistry , biology , psychiatry , in vitro
Aripiprazole is a recently approved drug for treating schizophrenia. It is often referred to as a 3 rd generation antipsychotic with unique clinical and biological properties. Its mechanism(s) of action has been attributed to either functionally selective properties or low partial agonist activity for D 2 receptor signaling. We have now evaluated the ability of aripiprazole, and 12 structurally related analogs (Vangveravong et al., 2011), to regulate D 2 receptor‐β‐arrestin‐2 interactions, an important signaling arm of the D 2 receptor. Two assays were employed to detect receptor‐arrestin interactions: 1) a bioluminescent resonance energy transfer (BRET) assay; and 2) a β‐galactosidsase complementation assay. In each assay, dopamine (DA) stimulates D 2 receptor‐β‐arrestin interactions in a dose‐dependently. None of the aripiprazole derivatives exhibited agonist activity, although each fully antagonized the DA response. Interestingly, when the DA dose‐response curves were performed with increasing concentrations of test ligand (Schild experiments), aripiprazole and four derivatives were found to decrease the EC MAX without affecting the EC 50 of DA (non‐competitive inhibition). In contrast, eight derivatives of aripiprazole decreased the EC 50 of DA without affecting the EC MAX (competitive inhibition). The structure‐activity relationships for these effects are currently under investigation.