title: Classics in Chemical Neuroscience: Aripiprazole.
abstract: Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2receptor 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 D2receptor 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 D2and D3and serotonin 5-HT1Areceptors, as well as antagonist activity at serotonin 5-HT2Areceptors, 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.
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Austen B
authors.initials: AB
authors.lastname: Casey
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Clinton E
authors.identifier: 0000-0002-7940-933X
authors.initials: CE
authors.lastname: Canal
mesh_terms: D014150:Antipsychotic Agents; D000068180:Aripiprazole
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole
keywords: 5-HT1A; 5-HT2A; 5-HT2B; Aripiprazole; D2; dopamine; receptors; schizophrenia; serotonin