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 analyzed in the rat central nervous system. At dopamine (DA) D1 ([3H]-SCH 23390) and D2 ([3H]-raclopride) binding sites, PUK showed IC50 values in the submicromolar range (0.4 and 0.6 microM, respectively). When the uptake of tritiated dopamine was assayed by using a synaptosomal preparation, PUK showed an IC50 = 46 microM. 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 perfused through a microdialysis probe inserted into the striatum, PUK (340 microM) induced a significant increase in dopamine levels. In vitro experiments with a crude rat brain mitochondrial suspension showed that PUK did not affect monoamine oxidase activities, at concentrations as high as 100 microM. PUK potently (IC50 = 15 microM) and dose-dependently inhibited the basal lipid 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 therapeutic strategies for Parkinson disease.
Dajas-Bailador
F A
FA
Division of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. bspfadb@bath.ac.uk
Asencio
M
M
Bonilla
C
C
Scorza
M C
MC
Echeverry
C
C
Reyes-Parada
M
M
Silveira
R
R
Protais
P
P
Russell
G
G
Cassels
B K
BK
Dajas
F
F
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001060:Aporphines / Q000494:pharmacology* / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015227:Lipid Peroxidation; D008297:Male; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy; D011597:Psychomotor Performance / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*
D000975:Antioxidants; D001060:Aporphines; D015259:Dopamine Agents; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D004298:Dopamine; C119869:pukateine