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NEUROPHARMACOLOGY

S32504, a Novel Naphtoxazine Agonist at Dopamine D₃/D₂ Receptors: I. Cellular, Electrophysiological, and Neurochemical Profile in Comparison with Ropinirole

Psychopharmacology Department (M.J.M., D.C., A.G., F.L., J.-M.R., C.M.L.C., A.N.-T.) and Chemistry B Department (J.-L.P.), Institut de Recherches Servier, Paris, France

S32504 [(+)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] displayed marked affinity for cloned, human (h)D₃ receptors (pK_i, 8.1) at which, in total G-protein ([³⁵S]GTPS binding, guanosine-5'-O-(3-[³⁵S]thio)-triphosphate), G_i3 (antibody capture/scintillation proximity), and mitogen-activated protein kinase (immunoblot) activation procedures, it behaved as an agonist: pEC₅₀ values, 8.7, 8.6, and 8.5, respectively. These actions were blocked by haloperidol and the selective D₃ receptor antagonist S33084 [(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl) benzamide)]. S32504 showed lower potency at hD_2S and hD_2L receptors in [³⁵S]GTPS binding (pEC₅₀ values, 6.4 and 6.7) and antibody capture/scintillation proximity (hD_2L, pEC₅₀, 6.6) procedures. However, reflecting signal amplification, it potently stimulated hD_2L receptor-coupled mitogen-activated protein kinase (pEC₅₀, 8.6). These actions were blocked by haloperidol and the selective D₂ receptor antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol]. The affinity of S32504 for hD₄ receptors was low (5.3) and negligible for hD₁ and hD₅ receptors (pK_i, <5.0). S32504 showed weak agonist properties at serotonin_1A ([³⁵S]GTPS binding, pEC₅₀, 5.0) and serotonin_2A (G_q, pEC₅₀, 5.2) receptors and low affinity for other (>50) sites. In anesthetized rats, S32504 (0.0025-0.01 mg/kg, i.v.) suppressed electrical activity of ventrotegmental dopaminergic neurons. Correspondingly, S32504 (0.0025-0.63 mg/kg, s.c.) potently reduced dialysis levels (and synthesis) of dopamine 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 transmission and failed to affect noradrenergic transmission. Actions of S32504 were expressed stereospecifically versus its less active enantiomer S32601 [(-)-trans-3,4,4a,5,6,10b-hexahydro-9-carbomoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine]. Although the D₃/D₂ agonist and antiparkinsonian 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.

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

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