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Research ArticleNEUROPHARMACOLOGY

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Hussien A. Al-Shamma, Christen Anderson, Emil Chuang, Remy Luthringer, Andrew J. Grottick, Erin Hauser, Michael Morgan, William Shanahan, Bradley R. Teegarden, William J. Thomsen and Dominic Behan
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 281-290; DOI: https://doi.org/10.1124/jpet.109.160994
Hussien A. Al-Shamma
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Christen Anderson
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Emil Chuang
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Remy Luthringer
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Andrew J. Grottick
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Erin Hauser
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Michael Morgan
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William Shanahan
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Bradley R. Teegarden
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William J. Thomsen
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Dominic Behan
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Abstract

5-Hydroxytryptamine (5-HT)2A receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT2A inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT2A receptor with at least 30- and 5000-fold selectivity compared with 5-HT2C and 5-HT2B receptors, respectively. Nelotanserin dosed orally prevented (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT2A agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.

Footnotes

  • This work was supported by Arena Pharmaceuticals Inc., San Diego, CA.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.160994

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CNS
    central nervous system
    5-HT
    5-hydroxytrptamine (serotonin)
    IP
    inositol phosphate
    DOI
    (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
    REM
    rapid eye movement
    NREM
    nonrapid eye movement
    SWS
    slow-wave sleep
    EEG
    electroencephalogram
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    AUC
    area under the plasma exposure curve
    MRT
    mean residency time
    EMG
    electromyogram
    β
    bregma
    AP
    anterioposterior
    ML
    mediolateral
    λ
    lambda
    PSG
    polysomnogram
    MCRT
    Multiple Choice Reaction Time
    CFFT
    Critical Flicker Fusion Test
    RAVLT
    Rey Auditory Verbal Learning Test
    ARCI-49
    Addiction Research Center Inventory
    VAS
    Visual Analog Scale
    DSST
    Digit Symbol Substitution Test
    LSEQ
    Leeds Sleep Evaluation Questionnaire
    GPCR
    G protein-coupled receptor
    CL/F
    clearance from plasma
    Vz/F
    volume of distribution.

    • Received August 27, 2009.
    • Accepted October 19, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleNEUROPHARMACOLOGY

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Hussien A. Al-Shamma, Christen Anderson, Emil Chuang, Remy Luthringer, Andrew J. Grottick, Erin Hauser, Michael Morgan, William Shanahan, Bradley R. Teegarden, William J. Thomsen and Dominic Behan
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 281-290; DOI: https://doi.org/10.1124/jpet.109.160994

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Research ArticleNEUROPHARMACOLOGY

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Hussien A. Al-Shamma, Christen Anderson, Emil Chuang, Remy Luthringer, Andrew J. Grottick, Erin Hauser, Michael Morgan, William Shanahan, Bradley R. Teegarden, William J. Thomsen and Dominic Behan
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 281-290; DOI: https://doi.org/10.1124/jpet.109.160994
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