The clinical utility of
dopamine (DA) D1 receptor agonists in the treatment of
Parkinson's disease (PD) is still unclear. The
therapeutic use of selective DA D1 receptor agonists such as
SKF-82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine hydrobromide) and
A-77636 ([1R, 3S] 3-[1'-admantyl]-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzo
pyran hydrochloride) seems limited because of their duration of action, which is too short for
SKF-82958 (< 1 hr) and too long for
A-77636 (> 20 hr, leading to behavioral tolerance). We therefore conducted the present acute dose-response study in four
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-exposed cynomolgus monkeys primed to exhibit
levodopa-induced
dyskinesias to evaluate the locomotor and dyskinetic effects on challenge with four doses (from 0.03 to 1.0 mg/kg) of
A-86929 ([-]-[5aR,11bS]-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-+ ++azacyclopent-1- ena[c]phenathrene-9-10-diol), a selective and full DA D1-like receptor agonist with an intermediate duration of action.
Levodopa and the DA D2-like receptor agonist, LY-171555 ([4aR-trans]-4,4a,5,6,7,8,8a,9-o-dihydro-5n-propyl-2H-pyrazo lo-3-4-
quinoline hydrochloride) were also used for comparison. Acute administration of
A-86929 was as efficacious in alleviating
MPTP-induced parkinsonism as
levodopa and LY-171555, but was less likely to reproduce the
levodopa-induced
dyskinesias in these animals than with either LY-171555 or subsequent challenge of
levodopa. Selective stimulation of the DA D1 receptor may provide better integration of neural inputs transmitted to the internal segment of the globus pallidus (referred to as the basal ganglia output) compared with
levodopa and selective DA D2 receptor agonist. Potent DA D1 receptor agents with an intermediate duration of efficacy such as
A-86929 (approximately 4 hr at higher doses tested) are potential therapeutic tools in PD and merit further attention.