The selective dopamine D1 receptor agonist A-86929 maintains efficacy with repeated treatment in rodent and primate models of Parkinson's disease

Abstract

The ability of the selective dopamine D1 receptor agonist (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-aza cyclopent-1-ena[c]-phenanthrene-9,10-diol (A-86929) to induce contralateral rotation after repeated administration was determined in rodent and primate models of Parkinson's disease. Testing was conducted in rats previously given unilateral 6-hydroxydopamine injections and in macaques previously given unilateral, intracarotid infusions of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Both treatments have been shown to reduce forebrain dopamine levels on the side of the infusion. Such animals rotate contralaterally after injections of direct-acting dopamine receptor agonists. Rats were administered A-86929 (0.11 or 0.22 micromol/kg s.c.) three times daily for 10 days, with injections spaced 3 h apart, and rotation was measured across a 9-h period on various treatment days. Initially, monkeys were given various doses of A-86929 (0.03, 0.10 or 0.30 micromol/kg i.m.), and rotation was monitored for 3 h after each dose. Significant, dose-dependent levels of contralateral rotation were achieved. Monkeys were next treated three times daily at 3-h intervals with A-86929 (0.3 micromol/kg). Analysis of total, daily rotation scores indicated that the magnitude of the behavioral response did not change significantly across the 10-day treatment period in monkeys, although it increased in rats (0.22 micromol/kg). The first daily injection tended to elicit greater and longer-lived responses than the subsequent daily injections in both species. In monkeys, this was particularly true on the first test day and was not seen by the last test. This study suggests that a selective D1 receptor agonist, such as A-86929, with full intrinsic activity relative to dopamine, may be useful for the treatment of Parkinson's disease.