In this study, we investigated antiparkinsonian activity of the novel, highly selective
dopamine D(2) receptor agonist
sumanirole compared with two clinically effective dopaminergic
therapies in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) primate model of
Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of
MPTP and subsequently dosed with vehicle,
L-DOPA plus
carbidopa (
L-DOPA),
ropinirole, or
sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that
sumanirole elicited improved functional outcome compared with vehicle. The
dopamine D2/D3 agonist
ropinirole improved behavioral outcome similar to
sumanirole, whereas
L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of
therapies that elicited normalization of PPRS was
L-DOPA >
sumanirole;
ropinirole did not normalize PPRS in any of the treated monkeys.
Dyskinesias were present with
L-DOPA treatment but were not observed in
sumanirole-,
ropinirole-, or placebo-treated primates. Pathologically, all
MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive
astrocytosis. Neurons immunoreactive with
antibodies to the nuclear
transcription factor DeltaFosB were most significantly increased in the striatum of
L-DOPA-treated monkeys. These results suggest that
sumanirole can exert antiparkinsonian effects similar to
L-DOPA without the behavioral and morphological consequences of the latter.