Repeated effects of asenapine on adrenergic and cholinergic muscarinic receptors

Choi, Yong Kee; Wong, Erik H. F.; Henry, Brian; Shahid, Mohammed; Tarazi, Frank I.

doi:10.1017/s1461145709990824

Cited by 17 publications

(9 citation statements)

References 22 publications

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“…This speculation is supported by the findings that asenapine has a relatively high occupancy of 5-HT 2A compared with the D 2 receptor, a profile similar to that of olanzapine (Meltzer et al, 2009); and chronic asenapine treatment increases D 2 receptor and decreases 5-HT 2A receptor binding in the medial prefrontal cortex (Tarazi et al, 2008, 2010), an effect also shared by olanzapine (Tarazi et al, 2001); and also by the findings that asenapine has a local 5-HT 2A receptor antagonistic activity in the medial prefrontal cortex and can dose-dependently increase extracellular dopamine release in this area (Franberg et al, 2012, 2008). Because chronic treatment of asenapine also alters other receptor systems, notably 5-HT 1A , D 4 , NMDA, and adrenergic α 1 and α 2 receptors (Choi et al, 2010; Franberg et al, 2012; Shahid et al, 2009; Tarazi and Neill, 2012), their involvement in asenapine sensitization also needs to be examined; and the two behavioral paradigms introduced in this study provide a valid approach in addressing this issue.…”

Section: Discussionmentioning

confidence: 99%

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Qin

Chen

2013

Neuropharmacology

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Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms – two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2–3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles.

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Section: Discussionmentioning

confidence: 99%

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Qin

Chen

2013

Neuropharmacology

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“…SNP has a very broad affinity spectrum toward CNS receptors, binding with antagonistic activity to serotonin 5‐HT 2C , 5‐HT 2A , 5‐HT 7 , 5‐HT 2B and 5‐HT 6 receptors, as well as to adrenergic α 2B , dopamine D 3 , histamine H 1 and H 2 and dopamine D 2S and D 2L ones, albeit with lower affinity . On the contrary, its activity toward muscarinic receptors is quite low, reducing the incidence of metabolic and cardiac side effects and sedation . It is due to this peculiarly wide receptor affinity profile that SNP has proven to be effective in bipolar disorder treatment.…”

Section: Introductionmentioning

confidence: 99%

Enantioseparation and determination of asenapine in biological fluid micromatrices by HPLC with diode array detection

Protti

Vignali

Blanco

et al. 2018

J of Separation Science

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Asenapine is a recent drug approved in the European Union for the treatment of bipolar disorder. An original approach has been developed for asenapine analysis in patients treated with the drug, including miniaturized microsampling procedures, separation and quantitation of drug enantiomers. An original enantioselective method based on high-performance liquid chromatography with diode array detection was developed and applied to the determination of asenapine enantiomer levels in innovative haematic samples: four micromatrices have been tested, two based on dried matrix spots (dried blood spots and dried plasma spots) and two based on volumetric absorptive microsampling (from blood and plasma). Chiral separation was achieved on a cellulose-tris(3,5 dimethylphenylcarbamate) column, with a mobile phase containing bicarbonate buffer and acetonitrile. The method was validated with satisfactory results of linearity and precision on all matrices that showed also a significant performance in terms of stability, feasibility and reliability, when compared to fluid plasma sampling, handling and processing. Among micromatrices, both volumetric absorptive microsampling types were superior to dried matrix spots in terms of data reproducibility and correspondence with plasma levels. The bioanalytical approach proposed herein provides for the first time a chiral high-performance liquid chromatographic method for the determination of asenapine enantiomers, coupled to a very effective microsampling strategy.

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“…Muscarinic antagonist effects could also deleteriously affect cognitive performance and may contribute to the deleterious effect on cognition observed with olanzapine and other atypical antipsychotics. Despite asenapine having no appreciable affinity for muscarinic receptors however, chronic asenapine administration (twice daily for 4 weeks) increased muscarinic receptor binding in the frontal cortex and hippocampal regions of rats [60]. These findings are consistent with the regionally specific asenapine-induced increases in AMPA and decreases in NMDA binding despite limited affinity for these receptors [61].…”

Section: Introduction To Asenapinementioning

confidence: 67%

Evaluation of the clinical efficacy of asenapine in schizophrenia

Minassian¹,

Young²

2010

Expert Opinion on Pharmacotherapy

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Importance of the field-Asenapine is a new atypical antipsychotic medication with high affinity for D 2 and 5HT 2A receptors that has been approved by the FDA in adults for the acute treatment of schizophrenia in the United States. The purpose of this review is to describe the compound and examine whether it addresses some of the unmet clinical needs in treating schizophrenia.Areas covered in this review-The development of asenapine is described with attention to its chemistry, pharmacodynamic and pharmacokinetic profile. Pre-clinical and clinical trials of safety and efficacy are reviewed. The advantages and disadvantages of asenapine relative to other antipsychotic medications are discussed.What the reader will gain-Asenapine will be evaluated for whether it: a) causes a reduction in symptoms of schizophrenia; b) has a side-effect profile minimizing extrapyramidal symptoms, weight gain, and cardiac effects; and c) affects negative and/or cognitive symptoms.Take home message-Asenapine is a recently approved agent with an acceptable cardiometabolic profile that exhibits similar efficacy as other antipsychotic medications, primarily on positive symptoms of schizophrenia. Relatively less weight gain compared to other agents may confer a notable advantage. Sublingual administration may have positive and negative effects on patient compliance. Potential "pro-cognitive" effects of asenapine are preliminary and require further investigation.

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Repeated effects of asenapine on adrenergic and cholinergic muscarinic receptors

Cited by 17 publications

References 22 publications

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Enantioseparation and determination of asenapine in biological fluid micromatrices by HPLC with diode array detection

Evaluation of the clinical efficacy of asenapine in schizophrenia

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