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Classics in Chemical Neuroscience: Aripiprazole.
ACS Chem Neurosci. 2017 06 21; 8(6):1135-1146.AC

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.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University , Boston, Massachusetts 02115, United States.Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University , Boston, Massachusetts 02115, United States.

Pub Type(s)

Journal Article
Review
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28368577

Citation

Casey, Austen B., and Clinton E. Canal. "Classics in Chemical Neuroscience: Aripiprazole." ACS Chemical Neuroscience, vol. 8, no. 6, 2017, pp. 1135-1146.
Casey AB, Canal CE. Classics in Chemical Neuroscience: Aripiprazole. ACS Chem Neurosci. 2017;8(6):1135-1146.
Casey, A. B., & Canal, C. E. (2017). Classics in Chemical Neuroscience: Aripiprazole. ACS Chemical Neuroscience, 8(6), 1135-1146. https://doi.org/10.1021/acschemneuro.7b00087
Casey AB, Canal CE. Classics in Chemical Neuroscience: Aripiprazole. ACS Chem Neurosci. 2017 06 21;8(6):1135-1146. PubMed PMID: 28368577.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Classics in Chemical Neuroscience: Aripiprazole. AU - Casey,Austen B, AU - Canal,Clinton E, Y1 - 2017/04/13/ PY - 2017/4/4/pubmed PY - 2018/5/2/medline PY - 2017/4/4/entrez KW - 5-HT1A KW - 5-HT2A KW - 5-HT2B KW - Aripiprazole KW - D2 KW - dopamine KW - receptors KW - schizophrenia KW - serotonin SP - 1135 EP - 1146 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 8 IS - 6 N2 - 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. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/28368577/Classics_in_Chemical_Neuroscience:_Aripiprazole_ L2 - https://dx.doi.org/10.1021/acschemneuro.7b00087 DB - PRIME DP - Unbound Medicine ER -
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