Antiparkinsonian effects of the novel D3/D2 dopamine receptor agonist, S32504, in MPTP-lesioned marmosets: Mediation by D2, not D3, dopamine receptors.
L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs. D3 receptors, an issue we addressed with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate model of Parkinson's disease. In L-dopa-primed animals, S32504 (0.16-2.5 mg/kg p.o.) dose-dependently enhanced locomotor activity. This action was abolished by the D2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug-naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D3/D2 agonist S32504 may offer advantages over L-dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D2, not D3, receptors.
Hill
Michael P
MP
Motac Neuroscience, Ltd., Manchester, United Kingdom. m.hill@motac.com
Ravenscroft
Paula
P
McGuire
Steven G
SG
Brotchie
Jonathan M
JM
Crossman
Alan R
AR
Rochat
Catherine
C
Millan
Mark J
MJ
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002144:Callithrix; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007211:Indoles / Q000627:therapeutic use; D007980:Levodopa / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D010078:Oxazines / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D050637:Receptors, Dopamine D3 / Q000502:physiology; D013997:Time Factors
D000978:Antiparkinson Agents; D018492:Dopamine Antagonists; D007211:Indoles; D010078:Oxazines; D010880:Piperidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C478818:S 32504; D007980:Levodopa; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole