Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
FEBS Lett ; 209(1): 122-8, 1986 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-3803571

RESUMEN

A series of 28 adenosine analogs and 17 xanthines has been assessed as inhibitors of binding of N6-R-[3H]phenylisopropyladenosine binding to A1 adenosine receptors in membranes from rat, calf, and guinea pig brain. Potencies of N6-alkyl- and N6-cycloalkyladenosines are similar in the different species. However, the presence of an aryl or heteroaryl moiety in the N6 substituent results in marked species differences with certain such analogs being about 30-fold more potent at receptors in calf than in guinea pig brain. Potencies at receptors in rat brain are intermediate. Conversely, 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine are about 10-fold less potent at receptors in calf brain than in guinea pig brain. Potencies of xanthines, such as theophylline, caffeine and 1,3-dipropylxanthine are similar in the different species. However, the presence of an 8-phenyl or 8-cycloalkyl substituent results in marked species differences. For example, a xanthine amine conjugate of 1,3-dipropyl-8-phenylxanthine is 9-fold more potent at receptors in calf than in rat brain and 110-fold more potent in calf than in guinea pig brain. Such differences indicate that brain A1 adenosine receptors are not identical in recognition sites for either agonists or antagonists in different mammalian species.


Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Corteza Cerebral/metabolismo , Receptores Purinérgicos/metabolismo , Xantinas/farmacología , Animales , Bovinos , Membrana Celular/metabolismo , Cobayas , Cinética , Fenilisopropiladenosina/metabolismo , Ratas , Receptores Purinérgicos/efectos de los fármacos , Relación Estructura-Actividad , Xantina
2.
J Med Chem ; 29(8): 1520-4, 1986 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3016270

RESUMEN

The effect of a variety of aryl substituents on the potency and selectivity of 19 analogues of 1,3-dipropyl-8-phenylxanthine as antagonists at A1- and A2-adenosine receptors in brain tissue was determined. The 4-sulfamoylphenyl and 4-carbamoylphenyl analogues are potent and somewhat selective for the A1 receptor. None of the dihydroxyphenyl analogues are remarkably potent, but all are selective for the A1 receptor. 1,3-Dipropyl-8-(2-hydroxy-4-methoxyphenyl)xanthine is the most selective A1 antagonist of the analogues with a A1/A2 potency ratio of about 90.


Asunto(s)
Receptores de Superficie Celular/metabolismo , Xantinas/farmacología , Animales , Corteza Cerebral/metabolismo , Ratas , Receptores Purinérgicos , Relación Estructura-Actividad , Xantinas/síntesis química
3.
J Med Chem ; 29(7): 1305-8, 1986 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-3806581

RESUMEN

A variety of analogues of caffeine and theophylline in which the 1-,3-, and 7-methyl substituents have been replaced with n-propyl, allyl, propargyl, and isobutyl and, in a few cases, with chloroethyl, hydroxyethyl, or benzyl were assessed for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Caffeine and theophylline are nonselective for these receptors. Nearly all of the 22 analogues of caffeine are more potent than caffeine itself at adenosine receptors. Replacement of the 1-methyl moiety with n-propyl, allyl, or propargyl substituent has little effect on potency at the A1 receptor while enhancing potency about 7- to 10-fold at the A2 receptor. 3,7-Di-methyl-1-propylxanthine is only slightly (1.4-fold) more potent than caffeine at the A1 receptor while being 10-fold more potent at the A2 receptor. 1,3-Di-n-propyl-7-methylxanthine is also selective for the A2 receptor, being 8-fold more potent than caffeine at the A1 receptor and 40-fold more potent at the A2 receptor. A number of other caffeine analogues including 3,7-dimethyl-1-n-propylxanthine, 7-allyl-1,3-dimethylxanthine, and 1,3-dimethyl-7-propargylxanthine are also somewhat selective for the A2 receptor. The most potent caffeine analogue was 1,3-di-n-propyl-7-propargylxanthine, which was about 100-fold more potent than caffeine at both A1 and A2 receptors. The 10 theophylline analogues were relatively nonselective except for the 1-ethyl analogue and the 1,3-diallyl analogue, which were selective for the A2 receptor, and the 1,3-di-n-propyl, 1,3-diisobutyl, and 1,3-dibenzyl analogues, which were somewhat selective for the A1 receptor. 1,3-Di-n-propylxanthine was 20-fold more potent than theophylline at the A1 receptor and 5-fold more potent at the A2 receptor.


Asunto(s)
Cafeína/análogos & derivados , Receptores Purinérgicos/metabolismo , Teofilina/análogos & derivados , Xantinas/síntesis química , Animales , Cafeína/síntesis química , Cafeína/farmacología , Membrana Celular/metabolismo , Corteza Cerebral/metabolismo , Indicadores y Reactivos , Espectrometría de Masas , Ratas , Receptores Purinérgicos/efectos de los fármacos , Relación Estructura-Actividad , Teofilina/síntesis química , Teofilina/farmacología
4.
J Med Chem ; 32(6): 1231-7, 1989 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-2724296

RESUMEN

The effects of 8-phenyl and 8-cycloalkyl substituents on the activity of theophylline, caffeine, 1,3-dipropylxanthine, 1,3-dipropyl-7-methylxanthine, 3-propylxanthine, and 1-propylxanthine at A1 adenosine receptors of rat brain and fat cells and at A2 adenosine receptors of rat pheochromocytoma PC12 cells and human platelets are compared. An 8-phenyl substituent has little effect on the activity of caffeine or 1,3-dipropyl-7-methylxanthine at adenosine receptors, while markedly increasing activity of theophylline, 1,3-dipropylxanthine, 1-isoamyl-3-isobutylxanthine, 1-methylxanthine, and 3-propylxanthine. 8-Phenyl-1-propylxanthine is potent (Ki = 20-70 nM) at all receptors. A p-carboxy or p-sulfo substituent, which is introduced on the 8-phenyl ring to increase water solubility, in most cases decreases the activity and selectivity for the A1 receptor. Among the 8-p-sulfo analogues, only 8-(p-sulfophenyl)theophylline and 1,3-dipropyl-8-(p-sulfophenyl)xanthine are selective for the A1 receptors. 8-p-Sulfophenyl derivatives of caffeine, 1,3-dipropyl-7-methylxanthine, and 3-propylxanthine are somewhat selective for the A2 receptors. 8-Cycloalkyl substituents (cyclopentyl, cyclohexyl) markedly increase activity of caffeine and 1,3-dipropyl-7-methylxanthine at the A2 receptor. 8-Cyclohexylcaffeine is potent (Ki = 190 nM) and very selective for the human platelet A2 receptors, but is not as selective for the rat PC12 cell A2 receptor. Such A2 selectivity is in contrast to the marked A1 selectivity of 8-cycloalkyltheophyllines and 8-cycloalkyl-1,3-dipropulxanthines. The apparent selectivity of certain xanthines is dependent on the assay systems that are compared.


Asunto(s)
Xantinas/farmacología , Adenilil Ciclasas/metabolismo , Tejido Adiposo/metabolismo , Neoplasias de las Glándulas Suprarrenales/metabolismo , Animales , Plaquetas/metabolismo , Encéfalo/metabolismo , Cafeína/farmacología , Fenómenos Químicos , Química , Humanos , Estructura Molecular , Fenilisopropiladenosina/metabolismo , Feocromocitoma/metabolismo , Ratas , Receptores Purinérgicos/efectos de los fármacos , Receptores Purinérgicos/metabolismo , Relación Estructura-Actividad , Teofilina/farmacología , Células Tumorales Cultivadas
5.
J Med Chem ; 31(3): 613-7, 1988 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-3346878

RESUMEN

A series of 1,3-dipropylxanthines were prepared with a variety of substituents at the 8-position. These included 8-aryl and 8-cycloalkyl groups. Polar carboxylate and carboxamide moieties were introduced as aryl substituents to increase water solubility. 1,3-Dipropyl-8-[2-hydroxy-4-[(carboxymethyl)oxy]phenyl]xanthine provided a functionalized congener with high potency (Ki = 37 nM) and selectivity (54-fold) for A1-adenosine receptors. This congener was used for preparation of a series of other analogues, some with higher potency and some with higher selectivity. 8-Cyclopentyl- and 8-cyclohexyl-1,3-dipropylxanthines were both very potent (Ki = 1-1.5 nM) and selective for A1 receptors, while 8-cycloalkylmethyl analogues were 10-fold less potent, but still very selective for A1 receptors. 8-Piperidinyl and 8-pyrazinyl analogues had very low activities as adenosine receptor antagonists.


Asunto(s)
Receptores Purinérgicos/efectos de los fármacos , Xantinas/síntesis química , Inhibidores de Adenilato Ciclasa , Animales , Cobayas , Humanos , Técnicas In Vitro , Cinética , Fenilisopropiladenosina/metabolismo , Ratas , Receptores Purinérgicos/metabolismo , Solubilidad , Relación Estructura-Actividad , Xantinas/metabolismo , Xantinas/farmacología
6.
J Med Chem ; 28(4): 487-92, 1985 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-2984420

RESUMEN

A series of 8-(substituted phenyl) derivatives of theophylline and other 1,3-dialkylxanthines were evaluated for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Theophylline has a similar potency (Ki = 14 microM) at both A1 and A2 receptors. 8-Phenyltheophylline is 25-35-fold more potent as an adenosine receptor antagonist than theophylline, while 8-phenylcaffeine is only 2-3-fold more potent than caffeine. A p-hydroxyaryl substituent enhances the potency of 8-phenyltheophylline as an adenosine antagonist. p-Carboxy- and p-sulfoaryl substituents reduce potency of 8-phenyltheophylline, yielding water-soluble adenosine antagonists, which are some 2-5-fold more potent than theophylline at adenosine receptors. None of the 8-(substituted phenyl)theophyllines are particularly selective as antagonists toward A1- and A2-adenosine receptors. 1,3-Dipropyl-8-phenylxanthine represents a potent and somewhat selective A1-receptor antagonist about 23-fold more potent at A1 receptors than at A2 receptors. A p-hydroxyaryl substituent further enhances potency of the 1,3-dipropyl-8-phenylxanthine at both A1 and A2 receptors. The 8-(2-amino-4-chlorophenyl)-1,3-dipropylxanthine is a very potent and selective antagonist for A1 receptors, being nearly 400-fold more potent at A1 than at A2 receptors. The water-soluble 8-(p-sulfophenyl)- and 8-(p-carboxyphenyl)-1,3-propylxanthines no longer exhibit marked selectivity. Both compounds are much more potent as adenosine antagonists than theophylline. The striking selectivity of 1-isoamyl-3-isobutylxanthine as an A1 antagonist is retained in the 8-phenyl derivative but is virtually lost in the 8-p-sulfophenyl derivative.


Asunto(s)
Adenosina/antagonistas & inhibidores , Receptores de Superficie Celular/efectos de los fármacos , Animales , Corteza Cerebral/metabolismo , Técnicas In Vitro , Ratas , Receptores Purinérgicos , Solubilidad , Relación Estructura-Actividad
7.
Biochem Pharmacol ; 39(12): 1897-904, 1990 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-2353933

RESUMEN

A variety of xanthines cause tracheal relaxation, an activity predictive of antiasthmatic potential. Structural analogs of caffeine, theophylline, and enprofylline were examined for their abilities to relax carbamylcholine-stimulated guinea pig trachea in vitro. All caffeine analogs tested were more potent than caffeine (EC50 = 551 +/- 81 microM) except the 8-p-sulfophenyl analog. 1,3,7-Tripropylxanthine and 1,3,7-tripropargylxanthine were among the more potent analogs with EC50 values of 12 +/- 1.3 and 65 +/- 11 microM respectively. Increasing the polarity at the 1- or 3-position by substituting a propargyl group for an n-propyl group decreased relaxant activity, an effect not observed at the 7-position. The 8-cyclohexyl-, 8-cyclopentyl- and 8-phenyl-derivatives of caffeine were relatively potent (EC 50 = approximately 75 microM). The theophylline analog 1,3-di-n-propylxanthine was approximately two times more active than theophylline (EC50 = 162 +/- 17 microM). 3-Isobutyl-1-methylxanthine (EC50 = 7.1 +/- 1.8 microM) and 1-isoamyl-3-isobutylxanthine (EC50 = 37 +/- 4.2 microM) were among the most potent tracheal relaxants. The 8-substituted theophylline analogs were weak or inactive relaxants except for 8-cyclopentyl- and 8-cyclohexyltheophylline, which were more potent or as potent as theophylline. In contrast to enprofylline (EC50 = 56 +/- 9 microM), 8-substituted enprofylline analogs were weak or inactive as relaxants with the exception of the 8-cyclohexyl analog. The potency of xanthines as tracheal relaxants was unrelated to potency as adenosine receptor antagonists and may reflect activity as phosphodiesterase inhibitors.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Cafeína/farmacología , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Teofilina/farmacología , Xantinas/farmacología , Animales , Cobayas , Técnicas In Vitro , Masculino , Receptores Purinérgicos/efectos de los fármacos , Tráquea/efectos de los fármacos
8.
Biochem Pharmacol ; 37(4): 655-64, 1988 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-2829919

RESUMEN

A variety of non-xanthine heterocycles were found to be antagonists of binding of [3H]phenylisopropyladenosine to rat brain A1-adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxamidoadenosine with A2-adenosine receptors in human platelet and rat phenochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A1- and A2-adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N6-substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A1 and A2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A1- and A2-adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and beta-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak non-competitive adenosine antagonist.


Asunto(s)
Adenosina/antagonistas & inhibidores , Compuestos Heterocíclicos/farmacología , Receptores Purinérgicos/efectos de los fármacos , Animales , Carbolinas/farmacología , Humanos , Imidazoles/farmacología , Técnicas In Vitro , Piridinas/farmacología , Ratas , Receptores de GABA-A/efectos de los fármacos , Relación Estructura-Actividad
9.
Life Sci ; 39(8): 743-50, 1986 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-3016449

RESUMEN

Several analogs of caffeine have been investigated as antagonists at A2 adenosine receptors stimulatory to adenylate cyclase in membranes from rat pheochromocytoma PC12 cells and human platelets and at A1 adenosine receptors inhibitory to adenylate cyclase from rat fat cells. Among these analogs, 1-propargyl-3,7-dimethylxanthine was about 4- to 7-fold and 7-propyl-1,3-dimethylxanthine about 3- to 4-fold more potent than caffeine at A2 receptors of PC12 cells and platelets. At A1 receptors of fat cells, both compounds were about 2-fold less potent than caffeine. These caffeine analogs have an A1/A2 selectivity ratio of about 10-20 and are the first selective A2 receptor antagonists yet reported. The results may provide the basis for the further development of highly potent and highly selective A2 adenosine receptor antagonists.


Asunto(s)
Cafeína/análogos & derivados , Receptores de Superficie Celular/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/antagonistas & inhibidores , Adenosina-5'-(N-etilcarboxamida) , Adenilil Ciclasas/metabolismo , Tejido Adiposo/enzimología , Neoplasias de las Glándulas Suprarrenales/enzimología , Animales , Plaquetas/enzimología , Cafeína/farmacología , Humanos , Fenilisopropiladenosina/antagonistas & inhibidores , Feocromocitoma/enzimología , Ratas , Receptores de Superficie Celular/clasificación , Receptores Purinérgicos , Relación Estructura-Actividad
10.
Life Sci ; 43(5): 387-98, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-2456442

RESUMEN

The behavioral stimulant effects of xanthines, such as caffeine and theophylline, appear to involve blockade of central adenosine receptors. However, 3-isobutyl-1-methylxanthine (IBMX), a potent phosphodiesterase (PDE) inhibitor, produces behavioral depression. The effects of caffeine analogs on open field behavior of mice and potencies as antagonists of adenosine receptors and as inhibitors of three classes of brain PDE have been compared. 1,7-Dimethyl-3-propargylxanthine, 1,3,7-tripropargylxanthine, and 3,7-dimethyl-1-propargylxanthine, which have high affinity for adenosine receptors and weaker activity as PDE inhibitors, all increase behavioral activity. In contrast, 1,3,7-tripropylxanthine, a more potent inhibitor of the brain calcium-independent (Ca-indep) PDEs than 1,3,7-tripropargylxanthine, produces behavioral depression, even though both analogues are potent adenosine receptor antagonists. 7-Benzyl-IBMX, an active receptor antagonist and selective inhibitor of a brain calcium-dependent (Ca-dep) PDE, produces a slight behavioral activation. Xanthines that are potent adenosine receptor antagonists and relatively weak inhibitors of the Ca-indep PDEs reverse the depressant effects of N6-cyclohexyladenosine, while xanthines, such as 1,3,7-tripropylxanthine, that are potent inhibitors of the Ca-indep PDEs, do not. The results suggest that the behavioral effects of xanthines may be determined primarily by relative activity as adenosine receptor antagonists and as inhibitors of brain Ca-indep PDEs.


Asunto(s)
Cafeína/análogos & derivados , Actividad Motora/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Receptores Purinérgicos/efectos de los fármacos , Teofilina/análogos & derivados , 1-Metil-3-Isobutilxantina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cafeína/farmacología , Calcio/fisiología , Técnicas In Vitro , Masculino , Ratones , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Teofilina/farmacología
11.
Life Sci ; 43(21): 1671-84, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-3193854

RESUMEN

3,7-Dimethyl-1-propargylxanthine (DMPX), a caffeine analog that exhibits in vitro selectivity for A2-adenosine receptors, compared to A1-adenosine receptors, has now been investigated with respect to in vivo potency and selectivity. DMPX potently and selectively blocked the actions of the potent A2 adenosine agonist, 5'-N-ethylcarboxamidoadenosine (NECA), in DBA/2 mice, compared to blockade of the same responses elicited by the selective A1-adenosine agonist, N6-cyclohexyladenosine (CHA). DMPX was 57-fold more potent versus NECA-induced hypothermia than versus CHA-induced hypothermia and 11-fold more potent versus NECA-induced behavioral depression than versus CHA-induced behavioral depression. The hypothermia is mediated by peripheral receptors, based on blockade by 8-(p-sulfophenyl)theophylline (PSPT), while the behavioral depression is centrally mediated, based on lack of blockade by PSPT. DMPX was 28- and 15-fold more potent than caffeine in blocking peripheral and central NECA-responses, respectively. DMPX was equipotent with caffeine versus CHA-induced hypothermia and 2.5-fold more potent than caffeine versus CHA-induced behavioral depression. The motor stimulating potency of DMPX (ED50 10 mumol/kg) was slightly greater than caffeine.


Asunto(s)
Adenosina/análogos & derivados , Temperatura Corporal/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Teobromina/análogos & derivados , Adenosina/antagonistas & inhibidores , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida) , Animales , Cafeína/farmacología , Masculino , Ratones , Ratones Endogámicos DBA , Valores de Referencia , Teobromina/farmacología , Teofilina/farmacología
12.
J Pharmacol Exp Ther ; 242(3): 882-7, 1987 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-3656117

RESUMEN

Caffeine, a nonselective adenosine receptor antagonist, 7-methyl-1,3-dipropylxanthine, a purported A2 selective antagonist and a 1,3-dipropyl-8-phenylxanthine amine congener (XAC), an A1 selective antagonist, were evaluated for their in vivo selectivity at A1 vs. A2 adenosine receptors. Blockade of the negative chronotropic effect of bolus i.v. injections of 2-chloroadenosine, R-phenylisopropyladenosine and N-ethylcarboxamidoadenosine was utilized as an index of antagonism at A1 receptors; blockade of the hypotensive effect of the same series of adenosine agonists was used as an index of activity at A2 receptors. In addition, blockade of the potentiating effect of adenosine on the hypertensive and chronotropic effects of nicotine was studied to assess further the role of A1 and A2 adenosine receptors in this response. The potent antagonist XAC displayed considerable A1 selectivity as demonstrated by blockade of adenosine receptor-mediated bradycardia at doses 5- to 10-fold lower than those antagonizing adenosine receptor-mediated hypotension. XAC also selectively blocked potentiation by adenosine of the positive chronotropic effect of nicotine, at doses which had minimal effects on the enhancement of the hypertensive effect of nicotine. The caffeine homolog 7-methyl-1,3-dipropylxanthine exhibited A2 selectivity as demonstrated by prevention of adenosine receptor-mediated hypotension at doses which only minimally attenuated the bradycardiac effect of adenosine analogs. Caffeine displayed no selectivity for A1 vs. A2 adenosine receptors. The results indicate that selective analogs such as XAC and F-methyl-1,3-dipropylxanthine will be useful probes for investigation of receptors involved in the physiological functions of adenosine.


Asunto(s)
Adenosina/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Receptores Purinérgicos/efectos de los fármacos , Adenosina/farmacología , Animales , Cafeína/análogos & derivados , Cafeína/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos , Nicotina/farmacología
13.
J Chem Ecol ; 11(3): 353-61, 1985 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24309967

RESUMEN

The volatile components of the Dufour's gland extracts ofDufourea novaeangliae were analyzed by gas chromatography-mass spectroscopy. The following were identified: a series of five bis-homologous unsaturated ketones ranging from C10 to C18, a series of nine bis-homologous hexanoates ranging from C8 to C24, a series of three bis-homologous octanoates ranging from C8 to C12, and hexanoic, hexadecanoic, and octadecanoic acids. The ketones are all new natural products reported for bees. Several of these unsaturated ketones were also identified in extracts of the provision masses from their nest cells. Male mandibular gland extracts contained citral.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA