Selective blockade of D(3) dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate.
To date, the lack of highly selective antagonists at the dopamine D(3) receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D(3) versus D(2) receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D(3)-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D(3) receptor stimulation. Indeed, stimulation of D(3) receptors may be detrimental to the anti-parkinsonian properties of D(2)/D(3) agonists. Selectivity for stimulation of D(2), over D(3), receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.
Silverdale
M A
MA
Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Nicholson
S L
SL
Ravenscroft
P
P
Crossman
A R
AR
Millan
M J
MJ
Brotchie
J M
JM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002144:Callithrix; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007211:Indoles / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011758:Pyrroles / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D050637:Receptors, Dopamine D3
D001578:Benzopyrans; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C408389:S 33084; C046649:ropinirole; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine