Potential therapeutic use of the selective dopamine D₁ receptor agonist, A-86929: An acute study in parkinsonian levodopa-primed monkeys

Abstract

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-benzazepine hydrobromide) and A-77636 ([1R, 3S] 3-[1′-admantyl]-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran 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-pyrazolo-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 agonists. 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.