dimetossi diidrossi aporfina

 

 

 DIMETOSSI-DIIDROSSI-APORFINA (contenuta nei prodotti Renalit Combi Colic e Adenomix-alfa)

 

La Dimetossi-diidrossi-aporfina è una sostanza di natura Alcaloidea estratta da una pianta sempreverde, Peumus Boldus Molina, originaria del Cile e del Perù appartenente all’ordine delle Laurales.
I farmaci per il trattamento dell’ipertrofia prostatica benigna comprendono il gruppo degli alfa-bloccanti o alfa litici, il gruppo degli inibitori della 5alfa-reduttasi e la mepartricina. I farmaci di prima linea per l’ipertrofia prostatica (IPB) sono rappresentati dagli alfa-bloccanti o alfa-litici. Questi farmaci bloccano i recettori alfa1 adrenergici presenti nel tessuto urogenitale, prostata e soprattutto collo vescicale, inducendo miorilassamento. La loro azione farmacologica è rapida, evidente già dopo la prima dose, ma si mantiene solo fino a quando il farmaco viene somministrato: cessata la terapia, si annulla l’effetto terapeutico. Approssimativamente, la terapia con alfa-litici comporta un miglioramento di 4-6 punti del punteggio IPSS (scala di valutazione dei sintomi dell’ipertrofia prostatica); sul lungo periodo non riduce però il rischio complessivo di ritenzione acuta d’urina o di intervento chirurgico (l’alfuzosin ha evidenziato un trend positivo, dopo 2 anni di terapia, di riduzione del rischio di intervento chirurgico in pazienti con un rischio di progressione di IPB maggiore rispetto a quello osservato nella popolazione dello studio MTOPS) (Emberton et al., 2008; Vallancien et al., 2008; Roehrborn, 2006). Gli alfa-bloccanti agendo sulla componente dinamica e non meccanica, ritardano la progressione dell’IPB ma non sono in grado di bloccarla (McConnell et al., 2003; Boyle, 2004).
Gli alfa-1 bloccanti selettivi- Il profilo farmacodinamico: i recettori alfa-1 sono localizzati nella muscolatura liscia non vascolare (come il trigono vescicale e gli sfinteri, il tratto gastrointestinale e gli sfinteri, la capsula della prostata e gli eventuali adenomi e gli ureteri) e nei tessuti non muscolari (come il sistema nervoso centrale, il fegato e i reni). Alcuni recettori alfa-1 sono localizzati nel corpo della vescica ma la maggior parte si trova sulla capsula della prostata o, in caso di IPB, sull’adenoma della prostata, oltreché nel trigono vescicale.MBloccando questi recettori è quindi possibile ridurre l’ostruzione dell’orifizio vescicale senza limitare la contrattilità della vescica Esistono almeno tre sottotipi di recettori alfa-1 adrenergici: l’alfa1A, l’alfa 1B e l’alfa 1D. Circa il 70% degli recettori alfa-1 della prostata appartiene al sottotipo alfa 1A(Emberton et al., 2008; Vallancien et al., 2008; Roehrborn, 2006)(McConnell et al., 2003; Boyle, 2004).

Uno studio condotto nel 2005 dal Dipartimento di Farmacologia dell’Università di Valencia (Spagna) evidenzia la capacità della “8-NH2-Boldina” di antagonizzare selettivamente gli adrenocettori α1A e α1B (Planta Med. 2005 Oct;71(10):897-903. 8-NH2-boldine, an antagonist of alpha1A and alpha1B adrenoceptors without affinity for the alpha1D subtype: structural requirements for aporphines at alpha1-adrenoceptor subtypes. Ivorra MD1, Valiente M, Martínez S, Madrero Y, Noguera MA, Cassels BK, Sobarzo EM, D’Ocon P.).

Qui sotto riportato lo studio:

 

Planta Med. 2005 Oct;71(10):897-903. 8-NH2-boldine, an antagonist of alpha1A and alpha1B adrenoceptors without affinity for the alpha1D subtype: structural requirements for aporphines at alpha1-adrenoceptor subtypes. Ivorra MD1, Valiente M, Martínez S, Madrero Y, Noguera MA, Cassels BK, Sobarzo EM, D’Ocon P.

 

Abstract
Structure-activity analysis of 21 aporphine derivatives was performed by examining their affinities for cloned human alpha (1A), alpha (1B) and alpha (1D) adrenoceptors (AR) using membranes prepared from rat-1 fibroblasts stably expressing each alpha (1)-AR subtype. All the compounds tested competed for [ (125)I]-HEAT binding with steep and monophasic curves. The most interesting compound was 8-NH (2)-boldine, which retains the selective affinity for alpha(1A)-AR (pKi = 6.37 +/- 0.21) vs. alpha(1B)-AR (pKi = 5.53 +/- 0.11) exhibited by 1,2,9,10-tetraoxygenated aporphines, but shows low affinity for alpha(1D)-AR (pKi < 2.5). Binding studies on native adrenoceptors present in rat cerebral cortex confirms the results obtained for human cloned alpha (1)-AR subtypes. The compounds selective for the alpha (1A) subtype discriminate two binding sites in rat cerebral cortex confirming a mixed population of alpha (1A)- and alpha (1B)-AR in this tissue. All compounds are more selective as inhibitors of [ (3)H]-prazosin binding than of [ (3)H]-diltiazem binding to rat cerebral cortical membranes. A close relationship was found between affinities obtained for cloned alpha (1A)-AR and inhibitory potencies on noradrenaline-induced contraction or inositol phosphate accumulation in tail artery, confirming that there is a homogeneous functional population of alpha(1A)-AR in this vessel. On the contrary, a poor correlation seems to exist between the affinity of 8-NH (2)-boldine for cloned alpha (1D)-AR and its potency as an inhibitor of noradrenaline-induced contraction or inositol phosphate accumulation in rat aorta, which confirms that a heterogeneous population of alpha (1)-AR mediates the adrenergic response in this vessel.

 
Un’altra pubblicazione sul “British Journal of Pharmacology” ha indagato la possibile determinante strutturale di selettività della boldina ed i suoi derivati per l’adrenocettore alfa-1A (Br J Pharmacol. 1996 Dec;119(8):1563-8. A possible structural determinant of selectivity of boldine and derivatives for the alpha 1A-adrenoceptor subtype. Madrero Y1, Elorriaga M, Martinez S, Noguera MA, Cassels BK, D’Ocon P, Ivorra MD.

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Br J Pharmacol. 1996 Dec;119(8):1563-8. A possible structural determinant of selectivity of boldine and derivatives for the alpha 1A-adrenoceptor subtype. Madrero Y1, Elorriaga M, Martinez S, Noguera MA, Cassels BK, D’Ocon P, Ivorra MD.

 

Abstract
The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9-O-methylboldine) and glaucine (2,9-O-dimethylboldine) and alpha 1-adrenoceptor subtypes was studied by examining [3H]-prazosin competition binding in rat cerebral cortex. WB 4101 and benoxathian were used as selective alpha 1A-adrenoceptor antagonists. 2. In the competition experiments [3H]-prazosin (0.2 nM) binding was inhibited by WB 4101 and benoxathian. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (pKi = 9.92 and 8.29 for WB 4101, 9.35 and 7.94 for benoxathian). The two antagonists recognized approximately 37% of the sites with high affinity from among the total [3H]-prazosin specific binding sites. 3. Boldine, predicentrine and glaucine also competed for [3H]-prazosin (0.2 nM) binding with shallow and biphasic curves recognizing 30-40% of the sites with high affinity. Drug affinities (pKi) at the high and low affinity sites were, 8.31 and 6.50, respectively, for boldine, 8.13 and 6.39 for predicentrine, and 7.12 and 5.92 for glaucine. The relative order of selectivity for alpha 1A-adrenoceptors was boldine (70 fold alpha 1A-selective) = predicentrine (60 fold, alpha 1A-selective) > glaucine (15 fold, alpha 1A-selective). 4. Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 microM) for 30 min at 37 degrees C followed by thorough washing out reduced specific [3H]-prazosin binding by approximately 70%. The CEC-insensitive [3H]-prazosin binding was inhibited by boldine monophasically (Hill slope = 0.93) with a single pKi value (7.76). 5. These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectively of action for the alpha 1A-adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2-hydroxy function, induces a significant increase in alpha 1A-subtype selectivity and affinity.

 

 

BIBLIOGRAFIA DI RIFERIMENTO:

1) ABOUD, R., SHAFII, M. & DOCHERTY, R.F. (1993). Investigations of subtypes of aI-adrenoceptor mediating contractions of rat aorta, vas deferent and spleen. Br. J. Pharmacol., 109, 80-87.
2) ASENSIO, M., CASSELS, B.K. & SPEISKY, H. (1993). The methylation of boldine with diazomethane. Bol. Soc. Chil. Quim., 38, 331-334.
3) BECKERINGH, J.J. & BRODDE, O.-E. (1989). ac-Adrenoceptorsubtypes in tissues of the rat and guinea-pig. Br. J. Pharmacol.,96, 154P.
4) BLUE, Jr, D.R., BONHAUS, D.W., FORD, A.P.D.W., PFISTER, J.R.,SHARIF, N.A., SHEIH, I.A., VIMONT, R.L., WILLIAMS, T.J. &CLARKE, D.E. (1995). Functional evidence equating the pharmacologically-defined alA- and cloned alc-adrenoceptor: studies inthe isolated perfused kidney of rat. Br. J. Pharmacol., 115, 283-294.
5) BOER, R., GRASSEGGER, A., SCHUDT, C. & GLOSSMANN, H. (1989).(+)-Niguldipine binds with very high affinity to Ca2+ channels and to a subtype of a1-adrenoceptors. Eur. J. Pharmacol.-Mol. Pharmacol. Sec., 172, 131-145.
6) BOLTON, T.B. (1979). Mechanism of action of transmitters and other substances on smooth muscle. Physiol. Rev., 85, 606- 719.
7) BRADFORD, M.M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye-binding. Anal. Biochem., 72, 248 -254.
8) CHULIA, S., IVORRA, M.D., LUGNIER, C., VILA, E., NOGUERA, M.A. & D’OCON, P. (1994). Mechanism of the cardiovascular activity of laudanosine: comparison with papaverine and other benzylisoquinolines. Br. J. Pharmacol., 113, 1377-1385.
9) COTECCHIA, S., SCHWINN, D.A., RANDALL, R.R., LEFKOWITZ, R.J., CARON, M.G. & KOBILKA, B.K. (1988). Molecular cloning and expression of the cDNA for the hamster a1-adrenergic receptor. Proc. Natl. Acad. Sci. U.S.A., 85, 7159-7163.
10) CUMISKEY, W.R. & FEIGENSON, M.E. (1983). Spasmolityc activity of cinnamedrine and papaverine in isolated rat uterine muscle. Arch. Int. Pharmacodyn. Ther., 263, 113 – 119.
11) ELTZE, M. & BOER, R. (1992). The adrenoceptor agonist, SDZ NVI 085, discriminates between alA- and alB-adrenoceptor subtypes in vas deferent, kidney and aorta of the rat. Eur. J. Pharmacol., 224, 125-136
12) FAURE, C., PIMOULE, C., ARBILLA, S., LANGER, S.Z. & GRAHAM, D. (1994). Expression of al-adrenoceptor subtypes in rat tissues: implications for a1-adrenoceptor classification. Eur. J. Pharmacol.- Mol. Pharmacol. Sec., 268, 141-149.
13) FORD, A.P.D.W., WILLIAMS, T.J., BLUE, D.R. & CLARKE, D.E. (1994). a1-Adrenoceptor classification: sharpening Occam’s razor. Trends Pharmacol. Sci., 15, 167- 170.
14) GRAZIADEI, I., ZERNING, G., BOER, R. & GLOSMAN, H. (1989). Stereoselective binding of niguldipine enantiomers to alAadrenoceptors labeled with 5-[3H]-methylurapidil. Eur. J. Pharmacol.-Mol. Pharmacol. Sec., 172, 329-337.
15) GROSS, G., HANFT, G. & RUGEVICS, C. (1988). 5-Methyl-urapidil discriminates between subtypes of the al-adrenoceptor. Eur. J. Pharmacol., 151, 333-335.
16) HAN, C., ABEL, P.W. & MINNEMAN, K.P. (1987a). Heterogeneity of a1-adrenergic receptors revealed by chlorethylclonidine. Mol. Pharmacol., 32, 505-510.
17) HAN, C., ABEL, P.W. & MINNEMAN, K.P. (1987b). a1-Adrenoceptor subtypes linked to different mechanisms for increasing intracellular Ca2+ in smooth muscle. Nature, 329, 333 – 335.
18) HAN, C. & MINNEMAN, K.P. (1991). Interaction of subtype-selective antagonist with a,-adrenergic receptor binding sites in rat tissues. Mol. Pharmacol., 40, 531 – 538.
19) HANFT, G. & GROSS, G. (1989a). Heterogeneity of a1-adrenoceptors binding sites in the rat heart-subtype selective agonists and antagonists. Br. J. Pharmacol., 98, 652P.
20) HANFT, G. & GROSS, G. (1989b). Subclassification of al-adrenoceptors recognition sites by urapidil derivatives and other selective antagonists. Br. J. Pharmacol., 97, 691-700.
21) HANFT, G., GROSS, G., BECKERINGH, J.J. & KORSTANJE, C. (1989). aI-Adrenoceptors: the ability of various agonists and antagonists to discriminate between two distinct [3H]-prazosin bindings sites. J. Pharm. Pharmacol., 41, 714-716.
22) HIEBLE, J.P., BYLUND, D.B., CLARKE, D.E., EIKENBURG, D.C., LANGER, S.Z., LEFKOWITZ, R.J., MINNEMAN, K.P. & RUFFOLO, R.R. (1995). International union of pharmacology X. Recommendation to nomenclature of ai-adrenoceptors: consensus
23) IVORRA, M.D., CHULIA, S., LUGNIER, C. & D’OCON, M.P. (1993). Selective action of two aporphines at a1-adrenoceptors and potential-operated Ca2 + channels. Eur. J. Pharmacol., 231, 165 -174.
24) IVORRA, M.D., LUGNIER, C., SCHOTT, C., CATRET, M., NOGUERA, M.A., ANSELMI, E. & D’OCON, P. (1992). Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, a1-adrenoceptor and benzothiazepine binding site at the calcium channel. Br. J. Pharmacol., 106, 387-394.
25) IVORRA, M.D., MADRERO, Y., NOGUERA, M.A., CASSELS, B.K. & D’OCON, P. (1995). Selective inhibition of alA-adrenoceptor subtype by (S)-boldine in rat cerebral cortex. Methods Find.Exp. Clin. Pharmacol., 17, (Suppl. A), 72.
26) KENNY, B.A., CHALMERS, D.H., PHILPOTT, P.C. & NAYLOR, A.M. (1995). Characterization of an MID- mediating the contractile response of rat aorta to noradrenaline. Br. J. Pharmacol., 115, 981 -986.
27) KENNY, B.A., NAYLOR, A.M., GREENGRASS, P.M., RUSSELL, M.J., FRIEND, S.J., READ, A.M. & WYLLIE, M.G. (1994). Pharmacological properties of the cloned alA/D-adrenoceptor subtype are consisted with the MlA-adrenoceptor characterized in rat cerebral cortex and vas deferens. Br. J. Pharmacol., 111, 1003-1008.
28) KO, F.N., GUH, J.H., YU, S.M., HOU, Y.S., WU, Y.C. & TENG, C.M.(1994). (-) Discretamine, a selective XID-adrenoceptor antagonist, isolated from Fissistigma glaucescens. Br. J. Pharmacol., 112,1174- 1180
29) .LOMASNEY, J.W., COTECCHIA, S., LORENZ, W., LEUNG, W.-Y.,SCHWINN, D.A., YANG-FENG, T.L., BROWNSTEIN, M., LEFKOWITZ, R.J. & CARON, M.G. (1991). Molecular cloning and expression of the cDNA for the alA-adrenergic receptor. J. Biol.Chem., 266, 6365-6369.
30) LUGNIER, C., BERTRAND, Y. & STOCLET, J.C. (1972). Cyclic nucleotide phosphodiesterase inhibition and vascular smooth muscle relaxation. Eur. J. Pharmacol., 19, 134- 136.
31) MARTINEZ, S., ELORRIAGA, M., CASSELS, B.K., D’OCON, P. & IVORRA, M.D. (1996). alA-adrenoceptor subtype selectivity of 9-0-methylboldine and glaucine in rat cerebral cortex: a structure -activity relationship study. Methods Find. Exp. Clin. Pharmacol.,18, (Suppl. B), 164.
32) MICHEL, M.C., KENNY, B. & SCHWINN, D.A. (1995). Classificationof ax-adrenoceptor subtypes. Naunyn-Schmiedeberg’s Arch.Pharmacol., 352, 1 -10.
33) MINNEMAN, K.P., HAN, C. & ABEL, P.W. (1988). Comparison of cxladrenergic receptor subtypes distinguished by chlorethylclonidine and WB-4101. Mol. Pharmacol., 33, 509- 514.
34) MORROW, A.L. & CREESE, I. (1986). Characterization of a, adrenergic receptor subtypes in rat brain: a reevaluation of [3H]
35) WB-4101 and [ H] prazosin binding. Mol. Pharmacol., 29, 321 -330.
36) MUNSON, P.J. & RODBARD, D. (1980). LIGAND: A versatilecomputerized approach for characterization of ligand-binding systems. Anal. Biochem., 107, 220-239.
37) O’HARA, N. & ONO, H. (1986). Papaverine inhibits binding of [3H]- prazosin and [3H]-yohimbine to rat renal cortical membranes. Res. Commun. Chem. Path. Pharmacol., 54, 157-171.
38) ORALLO, F., FDEZ ALZUETA, A., CAMPOS-TOIMIL, M. & CALLEJA, J.M. (1995). Study of the in vivo and in vitro cardiovascular effectof (+)-glaucine and N-carbethoxysecoglaucine in rats. Br. J. Pharmacol., 114, 1419 – 1427.
39) ORALLO, F., FDEZ ALZUETA, A., LOZA, M.I., VIVAS, N., BADIA, A., CAMPOS, M., HONRUBIA, M.A. & CADAVID, M.I. (1993). Study of the mechanism of the relaxant action of ( + )-glaucine in rat vas deferens. Br. J. Pharmacol., 110, 943-948.
40) ORIOWO, M.A. & RUFFOLO, Jr, R.R. (1992). Heterogeneity of postjunctional a1-adrenoceptors in mammalian aortae: subclassification based on chlorethylclonidine, WB4101 and nifedipine. J. Vasc. Res., 29, 33 – 40.
41) OSHITA,M., KIGOSHI, S. & MURAMATSU, I. (1991). Three distinct binding sites for [3H]-prazosin in the rat cerebral cortex. Br. J. Pharmacol., 104, 961 -965.
42) PEREZ, D.M., PIASCIK, M.T. & GRAHAM, R.M. (1991). Solutionphase library screening for the identification of rare clones:isolation of an avD adrenergic receptor cDNA. Mol. Pharmacol.,40, 876-883.
43) PEREZ, D.M., PIASCIK, M.T., MALIK, N. GAIVIN, R. & GRAHAM, R.M. (1994). Cloning expression, and tissue distribution of the rat homolog of the bovine alc adrenergic receptor provide evidence for its classification as the LIA subtype. Mol. Pharmacol., 46, 823-831.
44) PIASCIK, M.T., SMITH, M.S., SOLTIS, E.E. & PEREZ, D.M. (1994). Identification of the mRNA for the novel alD-adrenoceptor and two other an-adrenoceptors in vascular smooth muscle. Mol. Pharmacol., 46, 30-40.
45) PIASCIK, M.T., SPARKS, M.S., PRUITT, T.A. & SOLTIS, E.E. (1991). Evidence of a complex interaction between the subtypes of the aiadrenoceptor. Eur. J. Pharmacol., 199, 279 – 289.
46) PIMOULE, C., LANGER, S.Z. & GRAHAM, D. (1995). Further evidence that the classification a1A- and cloned alc-adrenoceptors are the same subtype. Eur. J. Pharmacol., 290, 49- 53.
47) REINHARDT, D., ROGGENBACH, W., SCHMIDT, U. & SCHUMANN, H.J. (1977). Effects of papaverine on the frequency-force relationship in guinea-pig left atria. Eur. J. Pharmacol., 41,123-126.
48) ROKOSH, D.G., BAILEY, B.A., STEWART, A.F.R., KARNS, L.R.,LONG, C.S. & SIMPSON, P.C. (1994). Distribution of aicadrenergic receptor mRNA in adult rat tissues by RNasa protection assay and comparison with aIB and nID. Biochem. Biophys. Res. Commun., 200, 1177 – 1184.
49) SALLES, J. & BADIA, A. (1994). Selective enrichment with XIA and Aib adrenoceptor subtypes in rat brain cortical membranes. Eur. J. Pharmacol.- Mol. Pharmacol. Sec., 266, 301 -308.
50) SCHWINN, D.A., LOMASNEY, J.W., LONENZ, W.P., SZKLUT, P.J., FREMEAU, R.T., YANG-FENG, T.L., CARON, M.G., LEFKOWITZ, R.J. & COTECCHIA, S. (1990). Molecular cloning and expression of the cDNA for a novel ao-adrenergic receptor subtype. J. Biol. Chem., 265, 8183-8189.
51) SPEISKY, H., CASSELS, B.K., LISSI, E.A. & VIDELA, L.A. (1991).Antioxidant properties of the alkaloid boldine in systemsundergoing lipid peroxidation and enzyme inactivation. Biochem. Pharmacol., 41, 1575-1582.
52) TESTA, R., GUARNERI, L., POGGESI, E., SIMONAZZI, I., TADDEI, C.& LEONARDI, A. (1995). Mediation of noradrenaline-induced contraction of rat aorta by the alB-adrenoceptor subtype. Br. J. Pharmacol., 114, 745-750.
53) VAN DER GRAAF, P.H., SHANKLEY, N.P. & BLACK, J.W. (1996). Analysis of the activity of a1-adrenoceptor antagonists in rat aorta. Br. J. Pharmacol., 118, 299-310.
Quanto proposto è ad esclusivo scopo informativo e non sostituisce il medico a cui bisogna rivolgersi per i problemi relativi alla salute.

 

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