α2-Adrenoceptors are targets for antipsychotic drugs

Brosda, Jan; Jantschak, Florian; Pertz, Heinz H.

doi:10.1007/s00213-014-3459-8

Cited by 41 publications

(48 citation statements)

References 154 publications

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“…Recent reviews, as well as older studies, have noted that the addition of agents that modulate NE α-2 receptor activity (e.g., IDAZ or mirtazapine) to typical antipsychotics (e.g., HAL) can increase their clinical antipsychotic efficacy and can reduce their extra-pyramidal side-effects (Brosda et al, 2014; Litman et al, 1996). Moreover, animal studies have noted that the addition of IDAZ to HAL can reduce conditioned avoidance response, suggesting greater efficacy for schizophrenia in a predictively valid model (Wadenberg et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan

Khokhar

Chau

Dawson

et al. 2015

Drug and Alcohol Dependence

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Background Alcohol use disorder commonly occurs in patients with schizophrenia. Most antipsychotic drugs do not lessen alcohol use; although the atypical antipsychotic clozapine has been shown to reduce alcohol use in patients with schizophrenia, its toxicity severely limits its use in patients. With an eye toward creation of a safer clozapine-like drug, we have investigated the pharmacological basis of the clozapine’s effects on alcohol drinking in the Syrian golden hamster. In this animal, as in patients with schizophrenia, clozapine reduces alcohol drinking while the typical antipsychotic haloperidol does not. We have suggested that clozapine decreases alcohol drinking due to its weak dopamine D2 receptor blockade, its potent norepinephrine α-2 receptor antagonism, as well as its ability to elevate plasma norepinephrine. Methods We recreated a clozapine-like drug to reduce alcohol drinking in the Syrian golden hamster by combining low dose haloperidol with a norepinephrine α-2 receptor antagonist, idazoxan, and a norepinephrine reuptake inhibitor, desipramine. Hamsters were given free access to water and alcohol (15% v/v) and were treated daily with each drug or with the three-drug combination for 23 days. Results The drug combination reduced alcohol drinking and preference significantly as compared to vehicle or to haloperidol, idazoxan or desipramine, while not altering food-intake or bodyweight. Conclusion These findings suggest that that haloperidol, which does not reduce alcohol drinking in patients with schizophrenia or the hamster, if combined with idazoxan and desipramine (producing a drug combination that mimics aspects of clozapine’s pharmacology) is able to reduce alcohol drinking in the hamster.

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Section: Discussionmentioning

confidence: 99%

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan

Khokhar

Chau

Dawson

et al. 2015

Drug and Alcohol Dependence

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“…These antipsychotic drugs are structurally similar to the sedative and anxiolytic benzodiazepines ( Table 1). The antipsychotic action of clozapine and olanzapine is deemed to be due to dopamine D2 receptor blockade, although interactions with other neurotransmitter receptors have been reported (Reynolds and Kirk 2010;Brosda et al 2014). The most common adverse effects of these compounds include GI manifestations, drowsiness, extrapyramidal symptoms, cardiac effects, elevation of liver enzymes, and obesity, which can be associated with insulin resistance and fatty liver (Melkersson and Dahl 2003;Begriche et al 2011;De Fazio et al 2015;Rojo et al 2015).…”

Section: Clozapine and Olanzapinementioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

181

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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“…A series of 4-aminoquinolines with different linker lengths (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) shown in Fig.1A were synthesized as described previously [8]. All synthesized compounds were identified by proton nuclear magnetic resonance and mass spectrometry ( Supplementary Information, Fig.…”

Section: The Affinity Of 4-aminoquinolines At α 2 -Arsmentioning

confidence: 99%

“…α 2 -ARs are mainly coupled to Gi protein and inhibit adenylyl cyclase activity, resulting in lower cAMP levels [1]. α 2 -ARs have been gradually recognized as promising antipsychotic therapeutic targets, especially for those associated with affective, psychotic, and cognitive symptoms [2]. α 2A -AR is widely distributed in central nervous system (CNS), accounting for 90% of α 2 -ARs, and is associated with regulation and strengthen of memory, analgesia, sedation, and has an anti-epileptic effect [3].…”

Section: Introductionmentioning

confidence: 99%

Structural insight into the mechanism of 4-aminoquinolines selectivity for the alpha2A-adrenoceptor

Liu

et al. 2019

Preprint

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α 2A -adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α 2A -AR agonists are one of the most effective drugs for this condition. However, the lack of high selectivity for α 2A -AR subtype of traditional drugs greatly limits their clinic usage. In this study, a series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α 2 -AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism. Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for the α 2A -AR over α 2B -and α 2C -ARs. Besides, the affinities are of similar linker length-dependence for each α 2 -AR subtype. Among all the compounds tested, C10 has the highest affinity for the α 2A -AR (pKi=-7.45±0.62), which is 12-fold and 60-fold selective over α 2B -AR and α 2C -AR, respectively. Docking and molecular dynamics studies suggest that C10 simultaneously interacts with an orthosteric and an "allosteric site" of the α 2A -AR. The mutation of F205, which is situated at the orthosteric binding pocket decreases the affinity by 2-fold. The potential allosteric residues include Ser90, Asn93, Glu94 and W99.The specificity of C10 for the α 2A -AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α 2A -AR subtype selective compounds.

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α2-Adrenoceptors are targets for antipsychotic drugs

Abstract: It is concluded that α2-adrenoceptors may be promising targets in the antipsychotic therapy.

Cited by 41 publications

References 154 publications

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan

Role of endoplasmic reticulum stress in drug‐induced toxicity

Structural insight into the mechanism of 4-aminoquinolines selectivity for the alpha2A-adrenoceptor

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