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

Richard Grondin, Paul J. Bédard, Donald R. Britton, Kazumi Shiosaki

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53 Scopus citations


The clinical utility of dopamine (DA)D1 receptor agonist 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-ally-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) and A-77636 ([1R,3S] 3-[1'-admantyl]-1-aminomethyl-3,4-dihydroxy-1H-2- benzopyran hydrochloride)) seems limited because of their duration off action, which is too short for SFK-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-azayclopent-1- ena[c]phenathrene-9-10-diol), a selective and full DA D1-like receptor agonist witth an intermediate duration of action. Levodopa an the A 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 the globus palidus (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.

Original languageEnglish
Pages (from-to)421-426
Number of pages6
Issue number2
StatePublished - Aug 1997

ASJC Scopus subject areas

  • Clinical Neurology


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