ABT-431 - THE DIACETYL PRODRUG OF A-86929, A POTENT AND SELECTIVE DOPAMINE D-1 RECEPTOR AGONIST - IN-VITRO CHARACTERIZATION AND EFFECTS IN ANIMAL-MODELS OF PARKINSONS-DISEASE

(-)-Trans xahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochlo ride (A-86929) is a potent and selective full agonist at the dopamine (DA)D-1-like receptor. Judging by its binding affinities to the D-1 an d D-2 classes of receptors, the compound is approximately 20-fold D-1 receptor-selective, whereas relative potencies based on functional in vitro assays indicate that A-86929 is greater than 400-fold D-1-select ive. A-86929 has moderate to weak (K-i > 1 mu M) affinity at other mon oaminergic and peptidergic receptors, at ion channels and at monoamine uptake sites. The catechol of A-86929 was bis-acetylated to produce t he prodrug, (-)-trans xahydro-3-thia-5-azacyclopent-1-ena[c]phenanthre ne hydrochloride (ABT-431), which is more chemically stable yet is rap idly converted to the parent compound with a half-life of less than 1 min in plasma. Both A-86929 and ABT-431 produced contralateral rotatio n in rats bearing unilateral 6-hydroxydopamine lesions, with ED(50) va lues of 0.24 mu mol/kg s.c. and 0.54 mu mol/kg s.c., respectively. A-8 6929 and ABT-431 improved behavioral disability scores and increased l ocomotor activity in the ethyl-4-phenyl-1,2,3,6-tetrahydropyridine-les ioned marmoset model of Parkinson's disease in a dose-dependent manner (the minimum effective dose was 0.10 mu mol/kg s.c.). When administer ed three times daily for 30 consecutive days to ethyl-4-phenyl-1,2,3,6 -tetrahydropyridine-lesioned marmosets, A-86929 significantly improved disability scores throughout the duration of the study. Current Parki nson's disease therapy includes L-dopa, which stimulates both classes of DA receptors by virtue of its conversion to DA in vivo, and direct- acting D-2-selective agonists. Stimulation of the D-2 receptor, which is associated with all current DA agonist-based therapies, may contrib ute to their dose-limiting side effects. An agent such as A-86929 (or its prodrug ABT-431), which selectively stimulates the D-1 receptor, m ay represent a novel mechanism for Parkinson's disease therapy with th e potential for an improved side-effect profile and, consequently, imp roved patient compliance.