Differential effect of selective D-1 and D-2 dopamine receptor agonists on levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- exposed monkeys

The motor effects of selective D-1 dopamine receptor stimulation in Parkinson's disease have been explored in a limited number of studies with partial D-1 agonists only and the results were unsatisfactory. Four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed parkinsonian monkeys already exhibiting levodopa- and dopamine agonist-induced dyskinesia received selective D-1 agonists ([2,3,4,5-tetrahydro-7-8-dihydroxy-1-phenyl-1-H-3-benzazepine- HCI] (SKF 38393), [(+-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrobromide] (SKF 82958), [(1R, 3S)3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6- dihydroxy-1H-2-benzopyran hydrochloride] (A-77636) and [(-)-(6aR)(12bR)-4,6,6a,7,8,12b-hexahydro-7-methyli ndolo (4,3-ab)-phenanthridine] (CY 208-243)) to compare these drugs with selective D-2 agonists (LY 171555, (+)-4-propyl-9- hydroxynaphthoxazine and bromocriptine) and levodopa in terms of antiparkinsonian efficacy and side effects. The D-1 class of compounds was as efficacious as the D-2 agents in alleviating parkinsonism in these animals. However, D-1 agonists were, in general, less likely to reproduce dyskinesia. In addition, D-1 agonists occasionally improved motor symptoms without concomitant dyskinesia, unlike D-2 agonists or levodopa (which always produced some dyskinesia with improvement in motor function). These preliminary results do not support the hypothesis that preferential D-1 receptor stimulation facilitates dyskinesia in primates.(ABSTRACT TRUNCATED AT 250 WORDS)