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Research ArticleNeuropharmacology

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

Mark J. Millan, Clotilde Mannoury la Cour, Benjamin Chanrion, Delphine S. Dupuis, Benjamin Di Cara, Valérie Audinot, Didier Cussac, Adrian Newman-Tancredi, Maud Kamal, Jean A. Boutin, Ralf Jockers, Philippe Marin, Joël Bockaert, Olivier Muller, Anne Dekeyne and Gilbert Lavielle
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 750-764; DOI: https://doi.org/10.1124/jpet.111.187468
Mark J. Millan
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Clotilde Mannoury la Cour
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Benjamin Chanrion
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Delphine S. Dupuis
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Benjamin Di Cara
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Valérie Audinot
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Didier Cussac
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Adrian Newman-Tancredi
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Maud Kamal
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Jean A. Boutin
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Ralf Jockers
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Philippe Marin
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Joël Bockaert
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Olivier Muller
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Anne Dekeyne
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Gilbert Lavielle
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Abstract

Although most antidepressants suppress serotonin (5-HT) and/or noradrenaline reuptake, blockade of 5-HT2C receptors and α2-adrenoceptors likewise enhances monoaminergic transmission. These sites are targeted by the urea derivative N- [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide (S32212). S32212 was devoid of affinity for monoamine reuptake sites, yet displayed pronounced affinity (pKi, 8.2) for constitutively active human 5-HT2CINI (h5-HT2CINI) receptors, behaving as an inverse agonist in reducing basal Gαq activation, [3H]inositol-phosphate production, and the spontaneous association of h5-HT2CINI-Renilla luciferase receptors with β-arrestin2-yellow fluorescent protein. Furthermore, upon 18-h pretreatment, S32212 enhanced the plasma membrane expression of h5-HT2CINI receptors as visualized by confocal microscopy and quantified by enzyme-linked immunosorbent assay. Its actions were prevented by the neutral antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl]indoline-1-carboxamide (SB242,084), which also impeded the induction by long-term exposure to S32212 of otherwise absent Ca2+ mobilization in mouse cortical neurones. In vivo, S32212 blunted the inhibitory influence of the 5-HT2C agonist 2-(3-chlorobenzyloxy)-6-(1-piperazinyl)pyrazine (CP809,101) on ventrotegmental dopaminergic neurones. S32212 also blocked 5-HT-induced Gαq and phospholipase C activation at the h5-HT2A and, less potently, h5-HT2B receptors and suppressed the discriminative stimulus properties of the 5-HT2A agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane in rats. S32212 manifested marked affinity for human α2A- (pKi 7.2), α2B- (pKi 8.2), and α2C- (pKi 7.4) adrenoceptors, at which it abolished noradrenaline-induced recruitment of Gαi3, Gαo, adenylyl cyclase, and extracellular-regulated kinase1/2. Moreover, S32212 dose-dependently abolished the discriminative stimulus effects of the α2-adrenoceptor agonist (S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2′-(1′,2′,3′,4′-tetrahydronaphthalene)] (S18616). Finally, S32212 displayed negligible affinity for α1A-adrenoceptors, histamine H1 receptors, and muscarinic M1 receptors. In conclusion, S32212 behaves as an inverse agonist at h5-HT2C receptors and as an antagonist at human α2-adrenoceptors (and h5-HT2A receptors). Its promising profile in preclinical models potentially relevant to the treatment of depression is described in J Pharmacol Exp Ther 340:765–780, 2012.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.187468.

  • ABBREVIATIONS:

    MT
    melatonin
    5-HT
    serotonin
    h5-HT
    human 5-HT
    5-HTP
    5-hydroxytryptophan
    AR
    adrenoceptor
    h-AR
    human AR
    CHO
    Chinese hamster ovary
    HEK
    human embryonic kidney
    DOI
    1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
    ERK
    extracellular-regulated kinase
    [35S]GTPγS
    guanosine-5′-O-(3-[35S]thio)-triphosphate
    IP
    inositol phosphate
    NA
    noradrenaline
    PI
    phosphatidyl inositol
    PLC
    phospholipase C
    SPA
    scintillation proximity assay
    LiCl
    lithium chloride
    VTA
    ventral tegmental area
    YFP
    yellow fluorescent protein
    ANOVA
    analysis of variance
    ELISA
    enzyme-linked immunosorbent assay
    Rluc
    Renilla luciferase
    BRET
    bioluminescence resonance energy transfer
    PBS
    phosphate-buffered saline
    BSA
    bovine serum albumin
    S32212
    N- [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide
    SB242,084
    6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl]indoline-1-carboxamide
    S18616
    (S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4, 2′-(1′,2′,3′,4′-tetrahydronaphthalene)]
    CP809,101
    2-(3-chlorobenzyloxy)-6-(1-piperazinyl)pyrazine
    RX821,002
    {2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline}
    WAY100,635
    N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-trihydrochloride
    GR125,743
    N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide
    BRL43,694
    N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl-1-methyl-1H-indazol-3-carboxamide
    GR113,808
    1-methyl-1H-indole-3-carboxylic acid 1-[2-(methylsulfonamido)ethyl]piperidin-4-ylmethyl ester
    LSD
    d-lysergic acid diethylamide
    CGP12177
    4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one
    SCH23390
    (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
    GBR12935
    1-(2-diphenylmethoxyethyl)-4-(3-phenylpropyl)piperazine
    Ro41-1049
    N-(2-aminoethyl)-5-(3-fluorophenyl)-4-thiazolecarboxamide
    Ro19-6327
    N-(2-aminoethyl)-5-chloro-pyridine-2-carboxamide
    AFDX384
    N-[2-[2-[(dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide.

  • Received September 30, 2011.
  • Accepted November 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

5-HT2C Receptors, α2-Adrenoceptors, and Depression

Mark J. Millan, Clotilde Mannoury la Cour, Benjamin Chanrion, Delphine S. Dupuis, Benjamin Di Cara, Valérie Audinot, Didier Cussac, Adrian Newman-Tancredi, Maud Kamal, Jean A. Boutin, Ralf Jockers, Philippe Marin, Joël Bockaert, Olivier Muller, Anne Dekeyne and Gilbert Lavielle
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 750-764; DOI: https://doi.org/10.1124/jpet.111.187468

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Research ArticleNeuropharmacology

5-HT2C Receptors, α2-Adrenoceptors, and Depression

Mark J. Millan, Clotilde Mannoury la Cour, Benjamin Chanrion, Delphine S. Dupuis, Benjamin Di Cara, Valérie Audinot, Didier Cussac, Adrian Newman-Tancredi, Maud Kamal, Jean A. Boutin, Ralf Jockers, Philippe Marin, Joël Bockaert, Olivier Muller, Anne Dekeyne and Gilbert Lavielle
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 750-764; DOI: https://doi.org/10.1124/jpet.111.187468
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