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NEUROPHARMACOLOGY

S32504, a Novel Naphtoxazine Agonist at Dopamine D₃/D₂ Receptors: II. Actions in Rodent, Primate, and Cellular Models of Antiparkinsonian Activity in Comparison to Ropinirole

Psychopharmacology Department (M.J.M., B.D.C., A.G., M.B.) and Chemistry B Department (J.-L.P.), Institut de Recherches Servier, Paris, France; Motac Neuroscience Ltd., Manchester, United Kingdom (M.H., J.B., S.M., A.C.); Neurodegenerative Diseases Research Centre, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London, United Kingdom (M.J., L.S., P.J.); and Thomas H. Christopher Center for Parkinson's Disease Research Center, Sun Health Research Institute, Sun City, Arizona (J.N.J.)

These studies evaluated the potential antiparkinsonian properties of the novel dopamine D₃/D₂ receptor agonist S32504 [(+)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] in comparison with those of the clinically employed agonist ropinirole. In rats with a unilateral, 6-hydroxydopamine lesion of the substantia nigra, S32504 (0.0025–0.04 mg/kg, s.c.) more potently elicited contralateral rotation than S32601 [(-)-trans-3,4,4a,5,6, 10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth-[1,2-b]-1,4-oxazine (its less active enantiomer)], ropinirole, and L-3,4-dihydroxyphenylalanine (L-DOPA). Rotation elicited by S32504 was blocked by the D₂/D₃ receptor antagonists haloperidol and raclopride and by the D₂ antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D₃ 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]. As assessed by dialysis in both lesioned and nonlesioned animals, S32504 (0.04–2.5 mg/kg, s.c.) reduced striatal levels of acetylcholine. This effect was blocked by raclopride, haloperidol, and L741,626 but not S33084. In rats treated with reserpine, hypolocomotion was reversed by S32504 and, less potently, by ropinirole. In "unprimed" marmosets treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, both s.c. (0.01–0.04 mg/kg) and p.o. (0.04–1.25 mg/kg) administration of S32504 dose-dependently and rapidly (within 10 min) increased locomotor activity and reduced disability. Furthermore, S32504 dose-dependently reversed bradykinesia and improved posture in "L-DOPA-primed" animals, whereas eliciting less pronounced dyskinesia than L-DOPA. Finally, in terminally differentiated SH-SY5Y cells presenting a dopaminergic phenotype, S32504, but not S32601, abrogated the neurotoxic effects of 1-methyl-4-phenylpyridinium, an action inhibited by raclopride and S33084 but not L741,626. Ropinirole was weakly neuroprotective in this model. In conclusion, S32504 displays potent and stereospecific activity in rodent, primate, and cellular models of antiparkinsonian properties. Although activation of D₂ receptors is crucial to the motor actions of S32504, engagement of D₃ receptors contributes to its neuroprotective properties.

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: mark.millan{at}fr.netgrs.com

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