Vascular Activity of (-)-Anonaine, (-)-Roemerine and (-)-Pukateine, Three Natural 6a(R)-1,2-Methylenedioxyaporphines with Different Affinities for α₁-Adrenoceptor Subtypes

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

[¹²⁵I]-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

References

• 1 Orallo F. Pharmacological effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in several rat isolated tissues.  Planta Medica. 2003;  69 135-42
• 2 Indra B, Matsunaga K, Hoshino O, Suzuki M, Ogasawara H, Ohizumi Y. Structure-activity relationship studies with (±)-nantenine derivatives for α₁-adrenoceptor antagonist activity.  Eur J Pharmacol. 2002;  437 173-8
• 3 Indra B, Matsunaga K, Hoshino O, Suzuki M, Ogasawara H, Muramatsu I, Taniguchi T, Ohizumi Y. (±)-Domesticine, a novel and selective α_1D-adrenoceptor antagonist in animal tissues and human α₁-adrenoceptors.  Eur J Pharmacol. 2002;  445 21-9
• 4 Eltze M, Grebe T, Michel M C, Czyborra P, Ullrich B. Affinity profile at α₁- and α₂-adrenoceptor subtypes and in vitro cardiovascular actions of (+)-boldine.  Eur J Pharmacol. 2002;  443 151-68
• 5 Chang K C, Su M J, Peng Y I, Shao C C, Wu Y C. Mechanical effects of liriodenine on the left ventricular-arterial coupling in Wistar rats: pressure-stroke volume analysis.  Br J Pharmacol. 2001;  133 29-36
• 6 Ivorra M D, Lugnier C, Schott C, Catret M, Noguera M A, Anselmi E, D’Ocon P. Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, α₁-adrenergic receptor and benzothiazepine receptor site at the calcium channel.  Br J Pharmacol. 1992;  106 307-94
• 7 Ivorra M D, Chuliá S, Lugnier C, D’Ocon M P. Selective actions of two aporphines at α₁-adrenoceptors and potential operated Ca²⁺ channels.  Eur J Pharmacol. 1993;  231 165-74
• 8 Chuliá S, Ivorra M D, Cavé A, Cortes D, Noguera M A, D’Ocon M P. Relaxant activity of three aporphine alkaloids from Annona cherimolia on isolated aorta of rat.  J Pharm Pharmacol. 1995;  47 647-50
• 9 Madrero Y, Elorriaga M, Martinez S, Noguera M A, Cassels B K, D’Ocon P, Ivorra M D. A possible structural determinant of selectivity of boldine and derivatives for the α_1A-adrenoceptor subtype.  Br J Pharmacol. 1996;  119 1563-8
• 10 Ivorra M D, D’Ocon P, Cassels B K, Schwinn D. Structure activity relationships in a series of aporphine derivatives showing selective affinity for human cloned α_1A-adrenoceptors (abstract form).  Naunyn-Schmiedeberg’s Arch Pharmacol. 1998;  358 Suppl 2 R606, P 6.61
• 11 Martínez S, Madrero Y, Elorriaga M, Noguera M A, Cassels B, Sobarzo E, D’Ocon P, Ivorra M D. Halogenated derivatives of boldine with high selectivity for α_1A-adrenoceptors in rat cerebral cortex.  Life Sci. 1999;  64 1205-14
• 12 D’Ocon P, Schwinn D. Structure activity relationships in a series of apomorphine derivatives showing selective affinity for human cloned α_1D adrenoceptors (abstract form). Naunyn-Schmiedeberg’s Arch.  Pharmacol. 1998;  358 Suppl 2 R605, P 6.59
• 13 Hieble J P, Bylund D B, Clarke D E, Eikenburg D C, Langer S Z, Lefkowitz R J, Minneman K P, Ruffolo R R. International Union of Pharmacology X. Recommendation for nomenclature of α₁-adrenoceptors: consensus update.  Pharmacol Rev. 1995;  47 267-70
• 14 Schwinn D A, Johnston G I, Page S O, Mosley M J, Wilson K H, Worman N P, Campbell S, Fidock M A, Furnes L M, Parry-Smith D J, Peter B, Bailey D S. Cloning and pharmacological characterization of human α₁ adrenergic receptors: sequence corrections and direct comparison with other species homologues.  J Pharmacol Exp Ther. 1995;  272 134-42
• 15 Lugnier C, Shoeffter A, Le Bec A, Strouthou E, Stoclet J C. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta.  Biochem Pharmacol. 1986;  35 1743-51
• 16 Lugnier C, Schini V B. Characterization of cyclic nucleotide phosphodiesterases from cultured bovine aortic endothelial cells.  Biochem Pharmacol. 1990;  39 75-84
• 17 Gisbert R, Madrero R, Sabino V, Noguera M A, Ivorra M D, D’Ocon M P. Functional characterization of α₁-adrenoceptor subtypes in vascular tissues using different experimental approaches: a comparative study.  Br J Pharmacol. 2003;  138 359-68
• 18 Urzúa A, Cassels B K. Additional alkaloids from Laurelia philippiana and L. novae-zelandiae .  Phytochemistry. 1982;  21 773-6
• 19 Stoclet J C, Keravis T, Komas N, Lugnier C. Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiovascular diseases.  Exp Opin Invest Drugs. 1995;  4 1081-1100
• 20 Dajas-Bailador F A, Asencio M, Bonilla C, Scorza M C, Echeverry C, Reyes-Parada M, Silveira R, Protais P, Russell G, Cassels B K, Dajas F. Dopaminergic pharmacology and antioxidant properties of pukateine, a natural product lead for the design of agents increasing dopamine neurotransmission.  Gen Pharmacol. 1999;  32 373-9
• 21 Neumeyer J L. Synthesis and structure-activity relationships of aporphines as dopamine receptor agonists and antagonists. In: Phillipson JD, Roberts MF, Zenk MH, editors The chemistry and biology of isoquinoline alkaloids. Berlin, Heidelberg; Springer-Verlag 1985: pp 146-70