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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 20, 2004; DOI: 10.1124/jpet.103.062398

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Received for publication November 5, 2003.
Revised February 3, 2004.
Accepted for publication February 12, 2004.

S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: I. Cellular, electrophysiological and neurochemical profile in comparison to ropinirole

Mark J. Millan 1*, Didier Cussac 1, Alain Gobert 1, Francoise Lejeune 1, Jean-Michel Rivet 1, Clotilde Mannoury La Cour 1, Adrian Newman-Tancredi 1, Jean-Louis Peglion 1

1 Institut de Recherches Servier

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

Abstract

S32504 displayed marked affinity for cloned, human (h)D3 receptors (pKi, 8.1) at which, in total G-protein ([35S]GTP{gamma}S-binding), G{alpha}i3(antibody-capture/scintillation-proximity) and Mitogen-Activated-Protein Kinase (immunoblot) activation procedures, it behaved as an agonist: pEffective Concentration50 (pEC50) values, 8.7, 8.6 and 8.5, respectively. These actions were blocked by haloperidol and the selective D3 receptor antagonist, S33084. S32504 showed lower potency at hD2S and hD2L receptors in [35S]GTP{gamma}S binding (pEC50s, 6.4 and 6.7) and antibody-capture/scintillation-proximity (hD2L, pEC50, 6.6) procedures. However, reflecting signal amplification, it potently stimulated hD2L receptor-coupled Mitogen-Activated-Protein Kinase (pEC50, 8.6). These actions were blocked by haloperidol and the selective D2 receptor antagonist, L741,626. The affinity of S32504 for hD4 receptors was low (5.3), and negligible for hD1 and hD5 receptors (pKis, <5.0). S32504 showed weak agonist properties at serotonin1A ([35S]GTP{gamma}S-binding, pEC50, 5.0) and serotonin2A (Gq, pEC50, 5.2) receptors, and low affinity for other (>50) sites. In anaesthetized rats, S32504 (0.0025-0.01 mg/kg, i.v.) suppressed electrical activity of ventrotegmental dopaminergic neurones. Correspondingly, S32504 (0.0025-0.63 mg/kg, s.c.) potently reduced dialysis levels (and synthesis) of DA in striatum, nucleus accumbens and frontal cortex of freely-moving rats, actions blocked by haloperidol and L741,626, but not by S33084. In contrast, S32504 only weakly inhibited serotonergic, and failed to affect noradrenergic, transmission. Actions of S32504 were expressed stereospecifically versus its less active enantiomer, S32601. Though the D3/D2 agonist and antiparkinson agent, ropinirole, mimicked the profile of S32504, it was less potent. In conclusion, S32504 is a potent and selective agonist at dopamine D3 and D2 receptors.


Key words: D2 receptor, D3 receptor, G-protein, dialysis, striatum, ventral tegmental area


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