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

Millan MJ, Cussac D, Gobert A, Lejeune F, Rivet JM, Mannoury La Cour C, Newman-Tancredi A, Peglion JL.
J Pharmacol Exp Ther. 2004 Jun;309(3):903-20. Epub 2004 Feb 20.

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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 (pKi, 8.1) at which, in total G-protein ([35S]GTPgammaS binding, guanosine-5'-O-(3-[35S]thio)-triphosphate), Galpha(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 hD2S and hD2L receptors in [35S]GTPgammaS binding (pEC50 values, 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 [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 (pKi, <5.0). S32504 showed weak agonist properties at serotonin(1A) ([35S]GTPgammaS binding, pEC50, 5.0) and serotonin(2A) (Gq, 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.