Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with
dopamine to have antiparkinsonian efficacy of similar magnitude to
levodopa, without the same propensity for inducing
dyskinesia. To date, no such agent has been tested in humans.
ABT-431 is the
prodrug of
A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) 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 12-hour
levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating 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 events, the most common minor events being
nausea and
emesis,
dizziness, and
hypotension. Assuming that
ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first
dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with
Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke
dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and
dyskinesia in
Parkinson's disease.