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2017 ; 8
(6
): 1135-1146
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Classics in Chemical Neuroscience: Aripiprazole
#MMPMID28368577
Casey AB
; Canal CE
ACS Chem Neurosci
2017[Jun]; 8
(6
): 1135-1146
PMID28368577
show ga
Aripiprazole was the first antipsychotic developed to possess agonist properties
at dopamine D(2) autoreceptors, a groundbreaking strategy that presented a new
vista for schizophrenia drug discovery. The dopamine D(2) receptor is the crucial
target of all extant antipsychotics, and all developed prior to aripiprazole were
D(2) 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 D(2) 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 D(2) and D(3) and serotonin 5-HT(1A) receptors, as well as
antagonist activity at serotonin 5-HT(2A) 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.
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