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Review
. 2017 Jun 21;8(6):1135-1146.
doi: 10.1021/acschemneuro.7b00087. Epub 2017 Apr 13.

Classics in Chemical Neuroscience: Aripiprazole

Austen B Casey  1 , Clinton E Canal  1
Affiliations
Review

Classics in Chemical Neuroscience: Aripiprazole

Austen B Casey et al. ACS Chem Neurosci. .

Abstract

Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D2 receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D2 and D3 and serotonin 5-HT1A receptors, as well as antagonist activity at serotonin 5-HT2A receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

Keywords: 5-HT1A; 5-HT2A; 5-HT2B; Aripiprazole; D2; dopamine; receptors; schizophrenia; serotonin.

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Figures

Figure 1
Figure 1
Chemical structures of aripiprazole (OPC-14597, left) and its predecessor OPC-4392 (right).
Figure 2
Figure 2
PubMed-indexed citations containing “aripiprazole” in their Abstract (1995–2016).
Figure 3
Figure 3
Structures of phase I metabolites of aripiprazole (adapted from FDA document NDA No. 21-436). Dehydroaripiprazole is the major metabolite after chronic dosing, and is pharmacologically active.
Scheme 1
Scheme 1
Synthesis of aripiprazole reported in the primary literature.
See this image and copyright information in PMC

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