Abstract
We have studied the mechanism of action of three 6a(R )-1,2-methylenedioxyaporphines as vasorelaxant compounds. The alkaloids assayed showed different affinities for the three human cloned α1 -adrenoceptor (AR) subtypes stably expressed in rat-1 fibroblasts, showing lower affinity for α
1B -AR with regard to the α
1A - or α
1D -subtypes. These three natural compounds are more potent inhibitors of [3
H ]-prazosin binding than of [3
H ]-diltiazem binding to rat cerebral cortical membranes. As all these alkaloids inhibited noradrenaline (NA)-induced [3
H ]-inositol phosphate formation in cerebral cortex and rat tail artery, they may be safely viewed as α1 -AR antagonists, as is demonstrated by the vasorelaxant responses observed in isolated rat tail artery and/or aorta precontracted with NA. The alkaloids also inhibited the contractile response evoked by KCl (80 mM) but with a lower potency than that shown against NA-induced contraction. We have also examined their ability to inhibit the different forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aortic smooth muscle and endothelial cells, with negative results. We conclude that N- methylation favours the interaction of (R)- aporphines with all α1 -AR subtypes, and that the topography of the binding site recognizing the basic or protonated nitrogen atom is similar in all three α1 -AR subtypes. The presence of a hydroxy group at C-11 has different effects on the affinity for each α1 -AR subtype but decreases the affinity for Ca2+ channels. These results confirm and extend the view that subtle changes in the hydroxylation patterns on the aromatic ring of the aporphine structure affect the interactions of these compounds with the three α1 -AR subtypes in different ways, suggesting that the binding site recognizing the aporphine skeleton is different in each of the three subtypes.
Abbreviations
PDE:cyclic nucleotide phosphodiesterase
AR:adrenoceptor
NA:noradrenaline
[125 I]-HEAT:[125
I ]iodo-2[β-(4-hydroxyphenyl)-ethylamino-methyl]-tetralone
Key words
1,2-Methylenedioxyaporphines - human cloned α1 -adrenoceptor subtypes - rat cerebral cortex - rat aorta - rat caudal artery - cyclic nucleotide phosphodiesterases
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