JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

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

0022-3565/08/3242-587-599$20.00
JPET 324:587-599, 2008
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.107.126706v1
324/2/587    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Millan, M. J.
Right arrow Articles by Lavielle, G.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Millan, M. J.
Right arrow Articles by Lavielle, G.

NEUROPHARMACOLOGY

S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], 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, Clotilde Mannoury la Cour, Francesca Novi, Roberto Maggio, Valérie Audinot, Adrian Newman-Tancredi, Didier Cussac, Valérie Pasteau, Jean-A. Boutin, Thierry Dubuffet, and Gilbert Lavielle

Psychopharmacology (M.J.M., C.M.l.C., A.N.-T., D.C., V.P.), Molecular Pharmacology (V.A., J.-A.B.), and Chemistry (T.D., G.L.) Departments, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy sur Seine, Paris, France; and Neuroscience Department, University of Pisa, Pisa, Italy (F.N., R.M.)

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]phenylacetamide), displayed ~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, and risperidone displayed similar affinities for hD3, hD2L, and hD2S sites. In guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]-GTP{gamma}S) filtration assays, S33138 showed potent, pure, and competitive antagonist properties at hD3 receptors, displaying pKB and pA2 values of 8.9 and 8.7, respectively. Higher concentrations were required to block hD2L and hD2S receptors. Preferential antagonist properties of S33138 at hD3 versus hD2L receptors were underpinned in antibody capture/scintillation proximity assays (SPAs) of G{alpha}i3 recruitment and in measures of extracellular-regulated kinase phosphorylation. In addition, in cells cotransfected 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 weak 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 human serotonin (5-HT)2A 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 antagonized 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 not h{alpha}2A or h{alpha}2B adrenoceptors (<5.0). Finally, in contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 displayed negligible 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 versus hD2 receptors.

Received June 4, 2007; accepted November 14, 2007.

Address correspondence to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France. E-mail: mark.millan{at}fr.netgrs.com




This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
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.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.