POTENTIAL THERAPEUTIC USE OF THE SELECTIVE DOPAMINE D-1 RECEPTOR AGONIST, A-86929 - AN ACUTE STUDY IN PARKINSONIAN LEVODOPA-PRIMED MONKEYS

The clinical utility of dopamine (DA) D-1 receptor agonists in the tre atment of Parkinson's disease (PD) is still unclear. The therapeutic u se of selective DA D-1 receptor agonists such as SKF-82958 -allyl-1-ph enyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrobromide) and A-77636 ([1R , 3S] nomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride ) seems limited because of their duration of action, which is too shor t for SKF-82958 (<1 hr) and too long for A-77636 (>20 hr, leading to b ehavioral tolerance). We therefore conducted the present acute dose-re sponse study in four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPT P)-exposed cynomolgus monkeys primed to exhibit levodopa-induced dyski nesias to evaluate the locomotor and dyskinetic effects on challenge w ith four doses (from 0.03 to 1.0 mg/kg) of A-86929 ,11bS]-4,5,5a,6,7,1 1b-hexahydro-2-propyl-3-thia-5- azacyclopent-1-ena[c]phenathrene-9-10- diol), a selective and full DA D-1-like receptor agonist with an inter mediate duration of action. Levodopa and the DA D-2-like receptor agon ist, LY-171555 ([4aR-trans]-4,4a,5,6,7,8,8a,9-o-dihydro-5n- propyl-2H- pyrazolo-3-4-quinoline hydrochloride) were also used for comparison. A cute 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 stimu lation of the DA D-1 receptor may provide better integration of neural inputs transmitted to the internal segment of the globus pallidus (re ferred to as the basal ganglia output) compared with levodopa and sele ctive DA D-2 receptor agonists. Potent DA D-1 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 meri t further attention.