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.

Abstract

These studies evaluated the potential antiparkinsonian properties of the novel dopamine D(3)/D(2) 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 D(2)/D(3) receptor antagonists haloperidol and raclopride and by the D(2) antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D(3) 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 D(2) receptors is crucial to the motor actions of S32504, engagement of D(3) receptors contributes to its neuroprotective properties.

• Authors: Mark J Millan, Benjamin Di Cara, Michael Hill, Michael Jackson, Jeffrey N Joyce, Jonathan Brotchie, Steve McGuire, Alan Crossman, Lance Smith, Peter Jenner, Alain Gobert, Jean-Louis Peglion, Mauricette Brocco
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 309 Issue 3 Pg. 921-35 (Jun 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14978195 (Publication Type: Comparative Study, Journal Article)

Chemical References

• DRD3 protein, human
• Dopamine Agonists
• Dopamine Antagonists
• Drd3 protein, rat
• Indoles
• Neuroprotective Agents
• Oxazines
• Receptors, Dopamine D2
• Receptors, Dopamine D3
• S 32504
• ropinirole
• Levodopa
• Reserpine
• Acetylcholine

Topics

• Acetylcholine (metabolism)
• Animals
• Callithrix
• Cells, Cultured
• Disease Models, Animal
• Dopamine Agonists (pharmacology, therapeutic use)
• Dopamine Antagonists (pharmacology)
• Drug Interactions
• Dyskinesias (drug therapy, etiology)
• Electrophysiology
• Extracellular Space
• Humans
• Hypokinesia (chemically induced, drug therapy)
• Indoles (therapeutic use)
• Levodopa (pharmacology, therapeutic use)
• MPTP Poisoning (drug therapy)
• Male
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Oxazines (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Receptors, Dopamine D2 (agonists, metabolism)
• Receptors, Dopamine D3
• Reserpine (pharmacology)
• Rotation