Dopaminergic pharmacology and antioxidant properties of pukateine, a natural product lead for the design of agents increasing dopamine neurotransmission

The dopaminergic and antioxidant properties of pukateine [(R)-11-hydroxy-1, 2-methylenedioxyaporphine, PUK], a natural aporphine derivative, were analy zed in the rat central nervous system. At dopamine (DA) D-1 ([H-3]-SCH 2339 0) and D-1 ([H-3]-raclopride) binding sites, PUK showed IC50 values in the submicromolar range (0.4 and 0.6 mu M, respectively). When the uptake of tr itiated dopamine was assayed by using a synaptosomal preparation, PUK showe d an IC50 = 46 mu M. In 6-hydroxydopamine unilaterally denervated rats, PUK (8 mg/kg but not 4 mg/kg) elicited a significant contralateral circling, a behavior classically associated with a dopaminergic agonist action. When p erfused through a microdialysis probe inserted into the striatum, PUK (340 mu M) induced a significant increase in dopamine levels. In vitro experimen ts with a crude rat brain mitochondrial suspension showed that PUK did not affect monoamine oxidase activities, at concentrations as high as 100 mu M PUK potently (IC50 = 15 mu M) and dose-dependently inhibited the basal lipi d peroxidation of a rat brain membrane preparation. As a whole, PUK showed a unique profile of action, comprising an increase in extracellular DA, an agonist-like interaction with DA receptors, and antioxidant activity. Thus, PUK may be taken as a lead compound for the development of novel therapeut ic strategies for Parkinson disease. (C) 1999 Elsevier Science Inc. All rig hts reserved.