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Research ArticleArticle

S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)1A Agonist Properties: I. Receptorial and Neurochemical Profile in Comparison with Clozapine and Haloperidol

Mark J. Millan, Alain Gobert, Adrian Newman-Tancredi, Valérie Audinot, Françoise Lejeune, Jean-Michel Rivet, Didier Cussac, Jean-Paul Nicolas, Olivier Muller and Gilbert Lavielle
Journal of Pharmacology and Experimental Therapeutics September 1998, 286 (3) 1341-1355;
Mark J. Millan
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Alain Gobert
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Adrian Newman-Tancredi
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Valérie Audinot
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Françoise Lejeune
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Jean-Michel Rivet
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Didier Cussac
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Jean-Paul Nicolas
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Olivier Muller
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Gilbert Lavielle
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Abstract

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPγS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists. In distinction to haloperidol, S 16924 shared the marked affinity of clozapine for h5-HT2Aand h5-HT2C receptors. However, an important difference to clozapine (and haloperidol) was the high affinity of S 16924 for h5-HT1A receptors. At these sites, using a [35S]GTPγS binding model, both S 16924 and clozapine behaved as partial agonists, whereas haloperidol was inactive. In vivo, the agonist properties of S 16924 at 5-HT1Aautoreceptors were revealed by its ability to potently inhibit the firing of raphe-localized serotoninergic neurones, an action reversed by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe firing, and their actions were resistant to WAY 100,635. Similarly, S 16924 more potently inhibited striatal turnover of 5-HT than either clozapine or haloperidol. Reflecting its modest affinity for D2 (and D3) autoreceptors, S 16924 only weakly blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal, mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active. In the frontal cortex (FCX) of freely moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same samples. In contrast, although S 16924 also suppressed 5-HT levels in the striatum and nucleus accumbens, DA levels therein were unaffected. Clozapine mimicked this selective increase in DA levels in the FCX as compared to striatum and accumbens. In contrast, haloperidol modestly increased DA levels in the FCX, striatum and accumbens to the same extent. In distinction to S 16924, clozapine and haloperidol exerted little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In conclusion, S 16924 possesses a profile of interaction at multiple monoaminergic receptors comparable to that of clozapine and distinct to that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration of S 16924 decreases cerebral serotoninergic transmission and selectively reinforces frontocortical as compared to subcortical dopaminergic transmission. In line with these actions, S 16924 shows a distinctive profile of activity in functional (behavioral) models of potential antipsychotic activity (companion paper).

Footnotes

  • Send reprint requests to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290—Croissy-sur-Seine, Paris, France.

  • Abbreviations:
    AR
    adrenergic
    ANOVA
    analysis of variance
    CHO
    Chinese hamster ovary
    DA
    dopamine
    DOPA
    dihydroxyphenylalanine
    DOPAC
    dihydroxyphenylacetic acid
    DRN
    dorsal raphe nucleus
    EC50
    effective concentration50
    FCX
    frontal cortex
    GTPγS
    guanylyl 5′-[γ-thio]-triphosphate
    5-HT
    serotonin
    5-HTP
    5-hydroxytryptophane
    HPLC
    high-performance liquid chromatography
    NAD
    noradrenaline
    VTA
    ventral tegmental area
    • Received February 4, 1998.
    • Accepted April 21, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 3
1 Sep 1998
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S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)1A Agonist Properties: I. Receptorial and Neurochemical Profile in Comparison …
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Research ArticleArticle

S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)1A Agonist Properties: I. Receptorial and Neurochemical Profile in Comparison with Clozapine and Haloperidol

Mark J. Millan, Alain Gobert, Adrian Newman-Tancredi, Valérie Audinot, Françoise Lejeune, Jean-Michel Rivet, Didier Cussac, Jean-Paul Nicolas, Olivier Muller and Gilbert Lavielle
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1341-1355;

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S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)1A Agonist Properties: I. Receptorial and Neurochemical Profile in Comparison with Clozapine and Haloperidol

Mark J. Millan, Alain Gobert, Adrian Newman-Tancredi, Valérie Audinot, Françoise Lejeune, Jean-Michel Rivet, Didier Cussac, Jean-Paul Nicolas, Olivier Muller and Gilbert Lavielle
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1341-1355;
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