Atypical antipsychotics—recent findings and new perspectives

Lowe, John; Seeger, Thomas; Vinick, Fredric J.

doi:10.1002/med.2610080403

Cited by 32 publications

(43 citation statements)

References 129 publications

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“…The typical antipsychotic category includes the phenothiazines (e.g., chlorpromazine), the thioxanthenes (e.g., flupenthixol), and the butyrophenones (e.g., haloperidol) while the atypical antipsychotic category includes the tricyclic antipsychotics (e.g., clozapine), and the benzamides (e.g., amisulpride). All antipsychotics tend to block DA D2‐like receptors in the mesolimbic DA pathway; however, while atypical antipsychotics affect DA turnover in the mesolimbic system preferentially [15,16], typical antipsychotics less selectively inhibit cholinergic, histaminergic, and adrenergic systems in addition to the broad sweeping inhibition of DA neurotransmission in both mesocorticolimbic and nigrostiatal pathways [1]. As such, atypical antipsychotics have been found to be associated with fewer extrapyramidal side effects (EPS; 15–18), and there have been great efforts allocated to the development of novel atypical antipsychotics associated with reduced incidence of EPS [19].…”

Section: Developmentmentioning

confidence: 99%

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A Review of the Discovery, Pharmacological Characterization, and Behavioral Effects of the Dopamine D2‐Like Receptor Antagonist Eticlopride

Martelle

Nader

2008

CNS Neuroscience & Therapeutics

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Eticlopride is a substituted benzamide analog with high affinity and selectivity for dopamine (DA) D2-like receptors that was initially developed as a potential antipsychotic agent. A great deal of research has utilized this drug to better understand central DA receptor function, the role of D2-like receptors in behavior, and the influence of blockade of these receptors on several preclinical animal models. This review highlights research utilizing this drug and compares it to typical and atypical antipsychotics used clinically. First, we describe structure-activity relationships as it relates to binding at DA receptors and the consequences on behavior. This is followed by a discussion of several imaging strategies including the use of eticlopride for in vivo, in vitro, and ex vivo examination of DA D2-like receptor densities and function. Finally, we discuss the use of eticlopride in several behavioral models predictive of antipsychotic activity, extrapyramidal side effects (EPS), and learning and memory. While eticlopride is not used clinically, it remains a viable research tool for understanding DA receptor function and behavior.

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Section: Developmentmentioning

confidence: 99%

“…Of the antipsychotics, the substituted‐benzamides are a group of compounds that has proven useful for the design of selective DA D2‐like receptor antagonists [15,20–22]. Sulpiride, the prototypical benzamide, was noted for its neuroleptic effects as early as the mid‐ to late‐1970s [17,18].…”

Section: Developmentmentioning

confidence: 99%

A Review of the Discovery, Pharmacological Characterization, and Behavioral Effects of the Dopamine D2‐Like Receptor Antagonist Eticlopride

Martelle

Nader

2008

CNS Neuroscience & Therapeutics

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“…In recent years, vigorous research on atypical neuroleptics for schizophrenia has led to hopes of the development of more selective drugs (Lowe et al 1988;Herrling 1990). The symptoms of schizophrenia are classiÞed as positive or negative, and the e¤ects of antipsychotics di¤er between these two types of symptoms (Moller 1994).…”

Section: Introductionmentioning

confidence: 99%

Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine

Yamamoto

1997

Psychopharmacology

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Cortical and hippocampal EEGs in animal models of schizophrenia were compared to those obtained with psychotomimetics or antipsychotic agents by utilizing power spectral analysis. Models of positive schizophrenic symptoms were created with methamphetamine (MAP) and cocaine, and a model of both negative and positive symptoms was created with PCP. MAP caused a prolonged decrease in the cortical EEG power spectra, cocaine caused a marked decrease for a short time, and PCP produced no significant changes. In the hippocampal spectra, MAP induced a marked increase in the T2(6.0-7.9 Hz)/ T1(4.0-5.9 Hz) ratio, PCP caused a decrease of this ratio after an initial increase, and cocaine produced no significant change. (An increase in the T2/T1 ratio represents a shift of theta waves to higher frequencies.) Since apomorphine (a DA agonist) and MK-801 (an NMDA antagonist) caused the T2/T1 ratio to increase, positive schizophrenic symptoms caused by MAP may be related to the DA and NMDA systems. 3-PPP (a sigma agonist) caused biphasic changes similar to those induced by PCP. Haloperidol and chlorpromazine caused a decrease of the T2/T1 ratio. These results indicate that cortical and hippocampal EEG power spectra (especially the hippocampal T2/T1 ratio) can be used to characterize both qualitatively and quantitatively models of schizophrenia.

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“…In contrast to conventional neuroleptics, atypical antipsychotics have been shown to be effective against both positive and negative symptoms of schizophrenia while showing a reduced propensity to induce extrapyramidal effects [1]. The cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6, and CYP3A enzymes are responsible for the metabolism of many of these and other psychoactive compounds [2–8].…”

Section: Introductionmentioning

confidence: 99%

Comparative Cytochrome P450In VitroInhibition by Atypical Antipsychotic Drugs

et al. 2013

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The goal of this study was to assess in human liver microsomes the inhibitory capacity of commonly used antipsychotics on the most prominent CYP450 drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A). Chlorpromazine was the only antipsychotic that inhibited CYP1A2 activity (IC50 = 9.5 μM), whilst levomepromazine, chlorpromazine, and thioridazine significantly decreased CYP2D6-mediated formation of 1′-hydroxybufuralol (IC50 range, 3.5–25.5 μM). Olanzapine inhibited CYP3A-catalyzed production of 1′, and 4′-hydroxymidazolam (IC50 = 14.65 and 42.20 μM, resp.). In contrast, risperidone (IC50 = 20.7 μM) and levomepromazine (IC50 = 30 μM) showed selectivity towards the inhibition of midazolam 1′-hydroxylation reaction, and haloperidol did so towards 4′-hydroxylation (IC50 of 2.76 μM). Thioridazine displayed a K i of 1.75 μM and an inhibitory potency of 1.57 on CYP2D6, suggesting a potential to induce in vivo interactions. However, with this exception, and given the observed K i values, the potential of the assayed antipsychotics to produce clinically significant inhibitions of CYP450 isoforms in vivo seems limited.

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Atypical antipsychotics—recent findings and new perspectives

Cited by 32 publications

References 129 publications

A Review of the Discovery, Pharmacological Characterization, and Behavioral Effects of the Dopamine D2‐Like Receptor Antagonist Eticlopride

A Review of the Discovery, Pharmacological Characterization, and Behavioral Effects of the Dopamine D2‐Like Receptor Antagonist Eticlopride

Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine

Comparative Cytochrome P450In VitroInhibition by Atypical Antipsychotic Drugs

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