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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 16, 2007; DOI: 10.1124/jpet.107.126706

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Received for publication June 26, 2007.
Revised November 14, 2007.
Accepted for publication November 14, 2007.

S33138, A PREFERENTIAL DOPAMINE D3 VERSUS D2 RECEPTOR ANTAGONIST AND POTENTIAL ANTIPSYCHOTIC AGENT. I. RECEPTOR-BINDING PROFILE AND FUNCTIONAL ACTIONS AT G-PROTEIN COUPLED RECEPTORS

Mark J. Millan 1*, Clotilde Mannoury la Cour 1, Francesca Novi 2, Roberto Maggio 3, Valerie Audinot 1, Adrian Newman-Tancredi 4, Didier Cussac 5, Valerie Pasteau 1, Jean A. Boutin 1, Thierry Dubuffet 1, Gilbert Lavielle 1

1 Institut de Recherches Servier 2 University of Pisa 3 University of L'Aquila 4 Centre de Recherche Pierre Fabre 5 Institut de Recherche Pierre Fabre

* Address correspondence to: E-mail: mark.millan{at}fr.netgrs.com

Abstract

The novel, potential antipsychotic, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl acetamide), displayed {approx}25-fold higher affinity at human (h) dopamine D3 versus hD2L (long isoform) and hD2S (short isoform) receptors: pKi values, 8.7, 7.1 and 7.3, respectively. Conversely, haloperidol, clozapine, olanzapine, risperidone and other clinically-available antipsychotics displayed similar affinities for hD3 versus hD2L and hD2S sites. In [35S]GTP{gamma}S filtration assays at hD3 receptors, S33138 showed potent, pure and competitive antagonist properties against dopamine with pKB and pA2 (Schild) values of 8.9 and 8.7, respectively: higher concentrations were required to block hD2L and hD2S receptors. The preferential antagonist properties of S33138 at hD3 vs hD2L receptors were underpinned in antibody-capture/scintillation-proximity (SPA) assays of G{alpha}i3 recruitment and in measures of extracellular-regulated-kinase phosphorylation. In addition, in cells co-transfected with hD3 and hD2L receptors that assemble into heterodimers, S33138 blocked (pKB, 8.5) the inhibitory influence of quinpirole upon forskolin-stimulated cAMP formation. S33138 had low affinity for hD4 receptors (<5.0) but revealed modest antagonist activity at hD1 receptors (G{alpha}s/SPA, pKB, 6.3) and hD5 sites (adenylyl cyclase, 6.5). Modest antagonist properties were also seen at h5-HT2A receptors (G{alpha}q/SPA, pKB, 6.8 and inositol formation, 6.9) and at 5-HT7 receptors (adenylyl cyclase, pKB, 7.1). In addition, S33138 antagonised h{alpha}2C-adrenoceptors ([35S]GTP{gamma}S, 7.2; G{alpha}i3/SPA, 6.9; G{alpha}o/SPA, 7.3 and extracellular-regulated-kinase, 7.1) but neither h{alpha}2A nor h{alpha}2B-adrenoceptors (<5.0). Finally, S33138 displayed only low affinities for multiple subtypes of {alpha}1 adrenoceptor, muscarinic and histamine receptor. In conclusion, S33138 possesses a distinctive receptor-binding profile and behaves, in contrast to clinically-available antipsychotics, as a preferential antagonist at hD3 vs hD2 receptors.


Key words: D3 receptor, G-protein, MAP-kinase, antipsychotics, dopamine, schizophrenia


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M. J. Millan, F. Loiseau, A. Dekeyne, A. Gobert, G. Flik, T. I. Cremers, J.-M. Rivet, D. Sicard, R. Billiras, and M. Brocco
S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects
J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1212 - 1226.
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