Bromperidol, a new butyrophenone neuroleptic: A review

Dubinsky, Barry; McGuire, J.L.; Niemegeers, C. J. E.; Janßen, Paul; Weintraub, Howard; McKenzie, Brienne

doi:10.1007/bf00470578

Cited by 14 publications

(5 citation statements)

References 29 publications

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“…4b ). The top-ranked hit compound, bromperidol, is a close structural and functional analog of haloperidol 25 . Among the 9 known antipsychotic drugs identified in the screen, 6 were butyrophenone derivatives and 3 were tricyclics.…”

Section: Resultsmentioning

confidence: 99%

Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds

Bruni

Rennekamp

Velenich³

et al. 2016

Nat Chem Biol

132

134

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Many psychiatric drugs act on multiple targets and therefore require screening assays that encompass a wide target space. With sufficiently rich phenotyping, and a large sampling of compounds, it should be possible to identify compounds with desired mechanisms of action based on their behavioral profiles alone. Although zebrafish (Danio rerio) behaviors have been used to rapidly identify neuroactive compounds, it remains unclear exactly what kind of behavioral assays might be necessary to identify multi-target compounds such as antipsychotics. Here, we developed a battery of behavioral assays in larval zebrafish to determine if behavioral profiles could provide sufficient phenotypic resolution to identify and classify psychiatric drugs. Using the antipsychotic drug haloperidol as a test case, we found that behavioral profiles of haloperidol-treated animals could be used to identify previously uncharacterized compounds with desired antipsychotic-like activities and multi-target mechanisms of action.

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Section: Resultsmentioning

confidence: 99%

Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds

Bruni

Rennekamp

Velenich³

et al. 2016

Nat Chem Biol

132

134

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“…Each of these compounds exhibited different clinical efficacy. For instance, bromperidol ( 18 ) possesses a dopamine D 2 receptor binding affinity similar to that of haloperidol, yet it has an apparent elimination half-life of approximately 24 h, supporting a once-daily dose regimen [57]. Trifluperidol ( 19 ) is a more potent neuroleptic drug than haloperidol and has been studied in withdrawn and autistic patients with schizophrenia.…”

Section: Development Of Antipsychotics For the Treatment Of Schizophrmentioning

confidence: 99%

Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future

Snyder²,

Vanover³

2016

CTMC

211

141

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Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world’s population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the unintentional engagement of multiple pharmacological targets or even the excessive engagement of intended pharmacological targets can lead to undesired consequences and poor tolerability. In this article, we will review marketed typical and atypical antipsychotics and new therapeutic agents targeting dopamine receptors and other neurotransmitters for the treatment of schizophrenia. Representative typical and atypical antipsychotic drugs and new investigational drug candidates will be systematically reviewed and compared by reviewing structure-activity relationships, pharmacokinetic properties, drug metabolism and safety, pharmacological properties, preclinical data in animal models, clinical outcomes and associated side effects.

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“…Data for the four neuroleptics having low affinity for the dopamine D 2 receptors (remoxipride, perlapine, seroquel, and melperone) that have high radioligand-independent dissociation constants were omitted because these neuroleptics are atypical by virtue of being displaced by endogenous dopamine. Although clozapine and isoclozapine have identical D 2 :5-HT 2 A ratios, the catalepsy dose for clozapine is in excess of 100 mg/kg (arrow) The references for the catalepsy doses are: chlorpromazine (CPZ) (Janssen et al 1965;Stille et al 1965b;Dlabac et al 1975;Hunziker et al 1981;Dubinsky et al 1982;Gustafsson and Christensson 1990;Hirose et al 1990;Usuda et al 1981;Moore et al 1992); clozapine (Burki et al 1977;Moore et al 1992); fluphenazine (Janssen et al 1965); haloperidol (Halo.) (Stille et al 1965b;Burki et al 1977;Usuda et al 1981;Dubinsky et al 1982;Gustafsson and Christensson 1990;Hirose et al 1990;Hogberg et al 1990;Megens et al 1992;Moore et al 1992); isoclozapine (Stille et al 1965a;Schmutz 1973); isoloxapine (Schmutz and Eichenberger 1992); loxapine (Lox.)…”

Section: Balanced Block Of Dopamine D 2 Receptors and 5-ht 2 A Receptorsmentioning

confidence: 99%

Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors or Are Selective for D4 Receptors

Seeman

Corbett²,

Tol

1997

Neuropsychopharmacology

205

116

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This review examines the possible receptor basis of the atypical action of those atypical antipsychotic drugs that elicit low levels of Parkinsonism. Such an examination requires consistent and accurate dissociation constants for the antipsychotic drugs at the relevant dopamine and serotonin receptors. It has long been known, however, that the dissociation constant of a given antipsychotic drug at the dopamine D2 receptor varies between laboratories. Although such variation depends on several factors, it has recently been recognized that the radioligand used to measure the competition between the antipsychotic drug and the radioligand is an important variable. The present review summarizes information on this radioligand dependence. In general, a radioligand of low solubility in the membrane (i.e., low tissue:buffer partition) results in a low value for the antipsychotic dissociation constant when the drug competes with the radioligand. Hence, by first obtaining the antipsychotic dissociation constants using different radioligands of different solubility in the membrane, one can then extrapolate the data to low or "zero" ligand solubility. The extrapolated value represents the radioligand-independent dissociation constant of the antipsychotic. These values are here given for dopamine D2 and D4 receptors, as well as for serotonin 5-HT2A receptors. These values, moreover, agree with the dissociation constant directly obtained with the radioactive antipsychotic itself. For example, clozapine revealed a radioligand-independent value of 1.6 nM at the dopamine D4 receptor, agreeing with the value directly measured with [3H]-clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo concentration of clozapine (to occupy dopamine D4 receptors) can be derived to be about 13 nM, agreeing with the value of 12 to 20 nM in the plasma water or spinal fluid observed in treated patients. The atypical neuroleptics remoxipride, clozapine, perlapine, seroquel, and melperone had low affinity for the dopamine D2 receptor (radioligand-independent dissociation constants of 30 to 90 nM). Such low affinity makes these latter five drugs readily displaceable by high levels of endogenous dopamine in the caudate or putamen. Most typical neuroleptics have radioligand-independent values of 0.3 to 5 nM at dopamine D2 receptors, making them more resistant to displacement by endogenous dopamine. Finally, a relation was found between the neuroleptic doses for rat catalepsy and the D2:D4 ratio of the radioligand-independent K values for these two receptors. Thus, the atypical neuroleptics appear to fall into two groups, those that have a low affinity for dopamine D2 receptors and those that are selective for dopamine D4 receptors.

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Bromperidol, a new butyrophenone neuroleptic: A review

Cited by 14 publications

References 29 publications

Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds

Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds

Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future

Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors or Are Selective for D4 Receptors

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