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

From the Department of Pharmacology (Mr. Grondin and Dr. Bédard), Faculty of Medecine, Laval University and Centre de Recherche en Neurobiologie, Hôpital de l'Enfant-Jesus, Québec, Canada; and Neuroscience Research (Drs. Britton and Shiosaki), Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL.

Address correspondence and reprint requests to Dr. Paul J. Bédard, Centre de Recherche en Neurobiologie, Hôpital de L'Enfant-Jésus, 1401, rue Québec, Québec, Canada G1J 1Z4.

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.

Supported by the Medical Research Council of Canada, the Parkinson Foundation of Canada, and Abbott Laboratories, Abbott Park, IL.

Received November 13, 1996. Accepted in final form February 12, 1997.

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