The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D2 and serotonin 5-HT1A receptors

Heusler, Peter; Slot, L. Bruins; Tourette, Amélie; Tardif, Stéphanie; Cussac, Didier

doi:10.1016/j.ejphar.2011.07.031

Cited by 15 publications

(14 citation statements)

References 47 publications

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“…No attempt was made to correlate functional agonism, but the paucity of agonist activity at the eleven receptors screened suggests that agonism is less well predicted by binding affinity. In a few instances, the functional agonism detected did not correspond fully with published reports (Heusler et al, 2011;Jensen et al, 2008;Sur et al, 2003). Discrepancies could represent differential sensitivity to receptor activation in the different assays.…”

Section: Discussioncontrasting

confidence: 69%

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

et al. 2014

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Many neuropsychiatric drugs interact with more than one molecular target, and therapeutic indices might be improved by prospectively designing compounds with profiles optimized against a combination of targets. The dibenzo-epine scaffold is considered a privileged structure, and this scaffold has been explored rigorously in the search for potential novel neuropharmacologic treatments. Members of this chemical class are known to interact with many receptors and transporters, particularly those of the biogenic amine class. In this study, four points of diversity within a dibenzo-epine scaffold were varied systematically and the pharmacologic profiles of the compounds were assessed across 14 receptors and transporters thought to be important to clinical profiles of efficacy and safety. The resulting data were analyzed using a modified forward selection linear regression procedure, thus revealing potential pharmacophoric relationships of the assessed targets within this chemical class. The results highlight a strong covariance across numerous targets. Moreover, the outcome quantifies the innately problematic issue of prospectively designing compounds with defined affinities across multiple targets. Finally, an exploration of the correspondence of binding affinities to in vitro functional activity reveals an additional layer of complexity central to prospectively designing compounds to engage multiple targets. The apparent relatedness of the 5-HT(2a) and D₂ activities suggests that the structural pharmacophores of these receptors overlap more closely with each other than with members of their respective families.

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Section: Discussioncontrasting

confidence: 69%

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

et al. 2014

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“…It may be possible to design smart chemicals that do not engage the channel activation mechanism through the pocket but selectively block access to alcohol. Interestingly, numerous synthetic ligands have been reported to modulate GIRK channel function, including antidepressants (Kobayashi et al, 2004, 2011; Hamasaki et al, 2013), antipsychotics (Kobayashi et al, 2000; Heusler et al, 2011), and anesthetics (Slesinger, 2001; Yamakura et al, 2001; Zhou et al, 2001; Styer et al, 2010). Recently, a small compound was described that selectively activates heterotetramers containing the GIRK1 subunit and exhibits anti-epileptic properties (Kaufmann et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Alcohol modulation of G-protein-gated inwardly rectifying potassium channels: from binding to therapeutics

Bodhinathan

Slesinger

2014

Front. Physiol.

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Alcohol (ethanol)-induced behaviors may arise from direct interaction of alcohol with discrete protein cavities within brain proteins. Recent structural and biochemical studies have provided new insights into the mechanism of alcohol-dependent activation of G protein-gated inwardly rectifying potassium (GIRK) channels, which regulate neuronal responses in the brain reward circuit. GIRK channels contain an alcohol binding pocket formed at the interface of two adjacent channel subunits. Here, we discuss the physiochemical properties of the alcohol pocket and the roles of G protein βγ subunits and membrane phospholipid PIP2 in regulating the alcohol response of GIRK channels. Some of the features of alcohol modulation of GIRK channels may be common to other alcohol-sensitive brain proteins. We discuss the possibility of alcohol-selective therapeutics that block alcohol access to the pocket. Understanding alcohol recognition and modulation of brain proteins is essential for development of therapeutics for alcohol abuse and addiction.

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“…Smoking, a potent inducer of CYP1A2 enzyme activity, results in significantly lower clozapine serum concentrations in smokers compared with non-smokers [96]. N -Desmethylclozapine (norclozapine) and clozapine N- oxide are major metabolites of clozapine [97]. Studies have indicated that clozapine may be transformed by bioactivation to a chemically reactive nitrenium ion, which may play an important role in the pathogenesis of clozapine-induced agranulocytosis [98, 99].…”

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

212

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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The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D2 and serotonin 5-HT1A receptors

Cited by 15 publications

References 47 publications

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

Alcohol modulation of G-protein-gated inwardly rectifying potassium channels: from binding to therapeutics

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

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