ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease

Studies in animal models show a selective D1 receptor agonist with full Fun ctional efficacy compared with dopamine to have antiparkinsonian efficacy o f similar magnitude to levodopa, without the same propensity for inducing d yskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective BI receptor agonist. Subjects (n = 1 4) with levodopa-responsive Parkinson's disease received five doses of ABT- 431 (5, 10, 20, 30, and 40 mg) and one of placebo after a la-hour levodopa holiday. Response was assessed by using the Unified Parkinsons Disease Rati ng Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa, Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse ev ents, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unk nown active D2 metabolite, and remains selective for D1 receptors, it is th e first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings al so suggest that it may exhibit a reduced tendency to provoke dyskinesia. Th e emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyski nesia in Parkinson's disease.