RESUMO
Selective androgen receptor modulators (SARMs) represent an emerging class of drugs likely to be abused in sport. For clinical applications, these substances provide a promising alternative to testosterone-replacement therapies and their advantages include oral bioavailability, androgen receptor specificity, tissue selectivity, and the absence of steroid-related side effects. Although not yet commercially available, since January 2008 SARMs have been included on the prohibited list issued yearly by the World Anti-Doping Agency (WADA), so control laboratories need to update their procedures to detect either the parent drugs or their metabolites. Within this context, two quinolinone SARM models were synthesized and automatically characterized to update the existing routine screening procedures. The conditions for the new target analytes are compatible with the existing laboratory protocols used for both in-competition and out-of-competition controls and can be included in them. Validation parameters according to ISO 17025 and WADA guidelines were successfully determined. For analytical determinations, spiked urine samples were hydrolyzed and extracted at pH 9.6 with 10 mL of tert-butyl methyl ether. Then, the analytes were subsequently converted into trimethylsilyl derivatives and detected by gas chromatography-mass spectrometry. The absence of interferents, together with excellent repeatability of both retention times and the relative abundances of diagnostic ions, allowed proper identification of all SARM analytes. The analytes' quantification was linear up to 500 ng/mL and precision criteria were satisfied (coefficient of variation less than 25% at 10 ng/mL). The limits of detection were 1 ng/mL for both SARMs, whereas recovery values were between 95.5 and 99.3%. The validated method can be efficiently used for urine screening of the 2-quinolinone-derived SARMs tested.
Assuntos
Dopagem Esportivo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Quinolonas/análise , Receptores Androgênicos/efeitos dos fármacos , Humanos , Limite de Detecção , Espectroscopia de Ressonância Magnética , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
CAS 1609 (compound 1) and CHF 2363 (compound 2) are two furoxan derivatives able to release nitric oxide (NO) under physiological conditions, and display typical NO-dependent vasodilator activity. The potential genotoxic effects of compound 1 and of the water-soluble analogue of CHF 2363 (compound 2a) were investigated. The results show that the two compounds induce genotoxic effects only at concentrations that significantly reduce cell viability. However, in the case of compound 1 this range of concentrations is one order of magnitude higher than the one leading to the beneficial effects, while in the case of compound 2a these ranges partially overlap. In both cases the release of NO plays a key role in the induction of the cytotoxic and genotoxic effects, since the non-NO-donating furazan analogues display a different toxicological profile, and since the effects were reduced in the presence of oxyhaemoglobin, a well-known NO-scavenger.
Assuntos
Leucócitos Mononucleares/efeitos dos fármacos , Mutagênicos/toxicidade , Oxidiazóis/química , Oxidiazóis/toxicidade , Apoptose , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Humanos , Testes para Micronúcleos , Óxido Nítrico/metabolismo , Oxiemoglobinas/farmacologia , Solubilidade , Água/químicaRESUMO
An analytical procedure was developed for the fast screening of 16 diuretics (acetazolamide, althiazide, amiloride, bendroflumethiazide, bumetanide, canrenoic acid, chlorthalidone, chlorthiazide, clopamide, ethacrynic acid, furosemide, hydrochlorthiazide, hydroflumethiazide, indapamide, triamterene, trichlormethiazide) and a masking agent (probenecid) in human urine. The whole method involves three analytical steps, including (1) liquid/liquid extraction of the analytes from the matrix, (2) their reaction with methyl iodide at 70 degrees C for 2 h to form methyl derivatives, (3) analysis of the resulting mixture by fast gas chromatography/electron impact mass spectrometry (fast GC/EI-MS). The analytical method was validated by determining selectivity, linearity, accuracy, intra and inter assay precision, extraction efficiencies and signal to noise ratio (S/N) at the lowest calibration level (LCL) for all candidate analytes. The analytical performances of three extraction procedures and five combination of derivatization parameters were compared in order to probe the conditions for speeding up the sample preparation step. Limits of detection (LOD) were evaluated in both EI-MS and ECNI-MS (electron capture negative ionization mass spectrometry) modes, indicating better sensitivity for most of the analytes using the latter ionization technique. The use of short columns and high carrier gas velocity in fast GC/MS produced efficient separation of the analytes in less than 4 min, resulting in a drastic reduction of the analysis time, while a resolution comparable to that obtained from classic GC conditions is maintained. Fast quadrupole MS electronics allows high scan rates and effective data acquisition both in scan and selected ion monitoring modes.
Assuntos
Diuréticos/urina , Dopagem Esportivo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Detecção do Abuso de Substâncias/métodos , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The design of new vasodilator derivatives in which two different pharmacophoric groups are present in a single molecule has been pursued by substitution of NO-prodrug furoxan moieties for the furanylcarbonyl function in Prazosin, a well-known alpha 1-receptor antagonist. The aim was to obtain new antihypertensive agents in which two vasodilation mechanisms, alpha 1-antagonist and NO-mediated, can operate in an appropriate balance. The alpha 1-antagonist activity was assessed on rat aortic strips in the presence and in the absence of oxyhemoglobin (HbO2), a well-known scavenger of nitric oxide. The resulting hybrids displayed different pharmacological behaviors. When the 4-furoxanylcarbonyl system, bearing an ester or an amide function at the 3-position, was present (derivatives 7a,b), hybrids with predominant alpha 1-antagonist activity were obtained. By contrast, in the derivative 7c, in which the nitrile function is linked to the 3-position of the furoxan ring, the NO-mediated vasodilating properties are predominant. Finally, the (furoxanylsulfonyl)piperidine derivatives 13a,b showed NO vasodilation and alpha 1-antagonist activities in an appropriate balance. For the furoxan derivatives, the NO-dependent vasodilating ability, assessed on the K(+)-depolarized aortic strip, and the NO release features under the action of thiol cofactors are also discussed.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Anti-Hipertensivos/farmacologia , Óxido Nítrico/farmacologia , Oxidiazóis/farmacologia , Vasodilatadores/farmacologia , Antagonistas Adrenérgicos alfa/síntese química , Animais , Anti-Hipertensivos/química , Aorta , Cisteína/farmacologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Contração Muscular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Oxidiazóis/síntese química , Oxiemoglobinas/farmacologia , Prazosina/análogos & derivados , Prazosina/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
4-Phenyl-3-furoxancarbonitrile (2) affords nitric oxide under the action of thiol cofactors. Two principal products were isolated in the reaction with thiophenol: the phenylcyanoglyoxime (6) and 5-amino-3-phenyl-4-(phenylthio)isoxazole (7). Mechanisms which could account for the formation of these two products are discussed. Compound 2 is an efficient activator of the rat lung soluble guanylate cyclase, displays high vasodilatory activity on strips of rat thoracic aorta precontracted with noradrenaline, and is a potent inhibitor of platelet aggregation.
Assuntos
Óxido Nítrico/química , Oxidiazóis/química , Fenóis/química , Compostos de Sulfidrila , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Ativação Enzimática/efeitos dos fármacos , Guanosina Monofosfato/farmacologia , Guanilato Ciclase/metabolismo , Humanos , Pulmão/enzimologia , Masculino , Espectrometria de Massas , Norepinefrina/farmacologia , Oxidiazóis/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química , Vasodilatadores/farmacologiaRESUMO
The synthesis, characterization, NO donor properties, and in vitro vasodilating activity of a series of water soluble furoxans (5-14a,b) are described. All of the compounds released NO when treated with a large excess of cysteine under physiological conditions (pH 7.4; 37 degrees C). The amount of NO produced after 1 h of incubation was evaluated by detecting nitrites, via the Griess reaction. Derivatives 5b, 7b, and 14b were able to release nitric oxide also in the absence of the thiol cofactor. The initial rates of NO release were determined at different concentrations, using a spectrophotometric technique based on the NO-induced oxidation of oxyhemoglobin (HbO2) to methemoglobin (MetHb). The initial rates of NO release were linearly dependent on the concentrations of the single compounds. The vasodilating potency (EC50) of all the derivatives was assessed on rat aortic strips precontracted with noradrenaline. Correlation between potency and initial NO release rate is discussed.
Assuntos
Óxido Nítrico/metabolismo , Oxidiazóis/química , Vasodilatadores/química , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ratos , Solubilidade , Vasodilatadores/síntese química , Vasodilatadores/metabolismo , ÁguaRESUMO
A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Affinities to 1, 4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [3H]nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of EC50iGC/EC50 ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1, 4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Di-Hidropiridinas/síntese química , Doadores de Óxido Nítrico/síntese química , Oxidiazóis/síntese química , Vasodilatadores/síntese química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Ligação Competitiva , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Córtex Cerebral/metabolismo , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Técnicas In Vitro , Masculino , Azul de Metileno/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Nifedipino/farmacologia , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Vasodilatadores/química , Vasodilatadores/farmacologiaRESUMO
Synthesis of heteroaryl-ONN-azoxysulphones and pyrazolyl-ONN-azoxycyanides was carried out by the action of the appropriate reagents on the corresponding nitroso derivatives. Pyrazolyl-ONN-azoxyamides were obtained by hydrolysis of the corresponding cyanides. Synthesis of the arylsulphonylhydrazones was carried out by reacting R-substituted phenyl-sulphonylhydrazines on the isomers of methylfuroxancarbaldehyde. Cytotoxic activity was assessed on HeLa cells. Some of the compounds tested inhibit the colony-forming ability of the tumor cells at low concentrations.
Assuntos
Antineoplásicos/farmacologia , Células HeLa/efeitos dos fármacos , Humanos , Hidrazonas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologiaRESUMO
A series of analogues of prazosin, in which 1-methyl or 1-phenylpyrazole moieties were substituted for the furan ring, were synthesized and studied for their alpha 1-adrenoceptor antagonist activity. The role of the five member heterocyclic substructures in determining the affinity for the alpha 1-receptor is briefly discussed.
Assuntos
Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/síntese química , Prazosina/análogos & derivados , Pirazóis/química , Pirazóis/síntese química , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Modelos Moleculares , Músculo Liso Vascular/efeitos dos fármacos , Pirazóis/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
In the present work recent results obtained in the pharmacochemistry of the furoxan system are reported. In particular, after a brief description of the salient points of the furoxan chemistry, the synthesis and the properties of a series of Nifedipine and Prazosin analogues, containing this heterocyclic system, are described. Since we observed that a few furoxan derivatives are able to elicit both a dose-dependent rise in platelet cGMP levels and to promote a dose-dependent inhibition of AA-induced [Ca++] rise, and that many substituted furoxans show potent vasodilating and antiaggregatory activity, the possibility of using the furoxan system as a lead in the design of new vasodilators is also discussed.
Assuntos
Nifedipino/análogos & derivados , Oxidiazóis/farmacologia , Prazosina/análogos & derivados , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , GMP Cíclico/sangue , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Humanos , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Nifedipino/síntese química , Nifedipino/farmacologia , Oxidiazóis/química , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Prazosina/síntese química , Prazosina/farmacologia , Vasodilatadores/síntese química , Vasodilatadores/farmacologiaRESUMO
A series of 1,2,5-thiadiazole-1-oxide derivatives has been synthesized and studied for its H2-antagonist properties. These derivatives can be considered derived from classical H2-antagonists in which the structure was deeply modified in order to evidence the minimal structural requirements for the activity. It was found that it is sufficient to have the 1,2,5-thiadiazole-1-oxide ring substituted with an alkylamino moiety and with an aliphatic chain linked to the hydroxy or ether group to achieve compounds as active as cimetidine. A few considerations on the binding on guinea-pig cerebral cortex of a series of H2-antagonists with more and more simplified structures are also reported.
Assuntos
Antagonistas dos Receptores H2 da Histamina/síntese química , Tiadiazóis/síntese química , Animais , Carbacol/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Histamina/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Técnicas In Vitro , Isoproterenol/farmacologia , Espectroscopia de Ressonância Magnética , Músculo Liso/efeitos dos fármacos , Tiadiazóis/farmacologiaRESUMO
A series of N-alkylamide derivatives of 4-amino-3-furoxancarboxylic acids 5a-11a and their oxidation products, the azo derivatives 5b-11b, were synthesised and studied for their vasodilating properties. All the products were able to release rat aorta strips precontracted with (-)noradrenaline. Azo derivatives proved to be 20-200 times more potent than the parent amines. The large variation of lipophilicity within the two series does not seem to influence significantly the activity. Experiments carried out in the presence of oxyhaemoglobin (HbO(2)) suggest the involvement of nitric oxide (NO*) in the vasodilation.
Assuntos
Compostos Azo/farmacologia , Oxidiazóis/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Compostos Azo/síntese química , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Óxido Nítrico/metabolismo , Oxidiazóis/síntese química , Oxiemoglobinas/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Vasodilatadores/síntese químicaRESUMO
A number of ranitidine analogues in which the diamino-1,2,5-thiadiazole 1-oxide substructure bearing alkyl chains of different length is present as the urea equivalent group, were synthesised and studied for their lipophilic and H2 antagonist properties. Derivatives which displayed a logP < or = 3 behaved as competitive antagonists of histamine at H2 receptors present on guinea pig right atrium. The remaining more lipophilic members of the series showed an insurmountable antagonism not completely reversible after prolonged washing. A binding study suggested that an increase in the length of alkyl chain gave rise to hydrophobic interactions with the receptor which were responsible for the apparent irreversible H2 antagonism shown by the higher homologues of the series.
Assuntos
Antagonistas dos Receptores H2 da Histamina/química , Antagonistas dos Receptores H2 da Histamina/farmacologia , Tiadiazóis/química , Animais , Córtex Cerebral/metabolismo , Cimetidina/análogos & derivados , Cimetidina/metabolismo , Cobaias , Átrios do Coração/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Some aryl-N(O) = N-X and heteroaryl-N(O) = N-CN compounds were synthetized and tested against a culture of HeLa cells. The results obtained show that the - N(O) = N beta CN function, a new cytostatic group, is useful in the design of potential antitumoral compounds.
Assuntos
Antineoplásicos/síntese química , Compostos Azo/síntese química , Sobrevivência Celular/efeitos dos fármacos , Cianetos/síntese química , Compostos Azo/farmacologia , Fenômenos Químicos , Química , Cianetos/farmacologia , Células HeLa , HumanosRESUMO
Nitric oxide (NO) and reactive oxygen species (ROS) are double-edged swords in reperfused hearts. The effects of a NO-donor and an antioxidant compound against ischemia/reperfusion were studied. The compounds were tested separately, as a mixture and as a new hybrid molecule containing both leads. Isolated rat hearts underwent 30 min global ischemia and 2 hrs reperfusion. Compounds were infused either at 1 or 10 microM concentrations during the first 20 min of reperfusion. Hybrid was also tested in the presence of mitochondrial K(+) ATP-sensitive (mKATP) channel blockade by 5-HD (100 microM). Reduction of infarct size and recovery of left ventricular developed pressure during reperfusion were evaluated. When given at 1 microM concentration, hybrid significantly improved all indices of protection; its beneficial effects were abolished by mKATP channel blockade. At the same concentration, mixture and NO-donor alone improved recovery of left ventricular developed pressure but did not reduce infarct size; antioxidant was ineffective. When given at 10 microM concentration, antioxidant and mixture improved all parameters of protection; NO-donor and hybrid were ineffective. Our data suggest that different signaling cascades could be elicited by low and high concentrations of antioxidant compound and/or NO-donor. It is likely that a different NO-induced release of reactive oxygen species via mKATP channel activation may play a pivotal role in affecting infarct size and post-ischemic contractile recovery.
Assuntos
Antioxidantes/metabolismo , Cardiotônicos/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Doadores de Óxido Nítrico/metabolismo , Animais , Antioxidantes/administração & dosagem , Cardiotônicos/administração & dosagem , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Lipídeos , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Doadores de Óxido Nítrico/administração & dosagem , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , SolubilidadeRESUMO
Synthesis and structural characterization of some ring-open analogues of Prazosin containing either the guanidine substructure or urea-equivalent groups are described. The opening of the pyrimidine ring in Prazosin is very important as far as the affinity for alpha 1-adrenoceptor is concerned. The pA2 values of the ring-open derivatives are 10(4)-10(5) fold lower than that of the parent. It is probable that the affinity decrease principally reflects a negative influence of the conformational factors in the interaction with the alpha 1-receptor. The derivative 5 containing the guanidine moiety, charged at physiological pH, is as active as the other derivatives containing the uncharged urea-equivalent groups. This behaviour indicates, in this class of compounds, the importance of H-bonding interactions with the receptor. When in the ring-open models the ethanediamino substructure is substituted for the piperazine ring additional decrease in activity occurs.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Prazosina/análogos & derivados , Prazosina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ducto Deferente/efeitos dos fármacosRESUMO
PURPOSE: To obtain new cardiovascular agents with mixed Ca2+-channel antagonistic and NO-donor properties, a series of "hybrid" 1,4-dihydropyridines (1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO. METHODS: Synthesis of the models was achieved by a modified Hantzsch approach. All of the final furoxan 1,4-DHPs were assessed for their ability to produce nitrite in the presence of a large excess of cysteine by the Griess reaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of methylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Affinities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, were determined through displacement experiments of [3H]-nitrendipine on rat cortex homogenates. RESULTS: Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) displayed vasodilating activity depending predominantly on their Ca2+-channel blocker properties. By contrast, some others (derivatives 17a, 17b, and 21) behaved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-dependent vasodilating activities. CONCLUSION: This work demonstrates the possibility of obtaining well-balanced hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individual evaluation of the NO-dependent vasodilator component and that due to Ca2+-channel blocking is proposed.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Fármacos Cardiovasculares/síntese química , Di-Hidropiridinas/síntese química , Doadores de Óxido Nítrico/síntese química , Óxido Nítrico/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Relação Dose-Resposta a Droga , Masculino , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/química , Vasodilatadores/farmacologiaRESUMO
Analogues of 3-amino-4-[2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino] furazan (1) containing carbonyl groups joined to the amino functions linked to the furazan system have been synthetized and investigated for their H2-antagonist properties on the isolated guinea pig right atrium. The presence of the carbonyl group lowers the activity in respect to the corresponding leads. The decrease in activity is only by 1-2 orders of magnitude in the 3-acylamino-furazan series versus inactivity in the 4-acylamino isomers and in the diacylated series.
Assuntos
Furanos/síntese química , Antagonistas dos Receptores H2 da Histamina/síntese química , Animais , Furanos/farmacologia , Cobaias , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Antagonistas dos Receptores H2 da Histamina/farmacologia , Técnicas In VitroRESUMO
The synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide) moieties, endowed with different NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid of affinity for K(ATP) channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experiments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K+ channels, while in the guanidine analogues, this mechanism seems to underlie this action.
Assuntos
Nicorandil/farmacologia , Oxidiazóis/farmacologia , Animais , Aorta Torácica/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Guanidinas/síntese química , Guanidinas/farmacologia , Concentração Inibidora 50 , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Nicorandil/análogos & derivados , Nicorandil/síntese química , Doadores de Óxido Nítrico/síntese química , Óxidos de Nitrogênio/metabolismo , Ressonância Magnética Nuclear Biomolecular , Oxidiazóis/síntese química , Canais de Potássio/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/farmacologiaRESUMO
PURPOSE: A series of derivatives having a propranolol-like moiety linked to NO-donor furoxan substructures were synthesized. The main objective of this investigation was to obtain agents with mixed NO-dependent vasodilating and beta-blocking activities. METHODS: Most of the target compounds were synthesized from the appropriate furoxans bearing XCH2CH2NH2 (X = O, S, SO2) chains at the 4 position of the ring, using Al(C2H5)3 in methylene chloride solution and (+/-)2,3-epoxypropyl 1-naphtyl ether. Two of the final products (X = CONH) were obtained by coupling the appropriate furoxancarboxylic acids with N-[2-hydroxy-3-(1-naphthoxy)propyl]-ethylenediamine. beta 1- and beta 2-blocking activities were examined on isolated guinea pig right atria and on guinea pig trachea respectively. Vasodilating properties were assessed on endothelium denuded strips of rat aorta. RESULTS: Some derivatives behave as well balanced "hybrids" displaying NO-dependent vasodilating and beta-blocking properties in the same concentration range. Some others display either prevalent beta-blocking or vasodilating activity. Generally speaking hybrid formation lowers the affinity for beta-receptors, in particular for beta 2-type, to give an increase in beta 1/beta 2 selectivity. CONCLUSIONS: The furoxan system is a flexible tool in designing analogues of propranolol whose NO-donating and beta-blocking properties are modulated over a wide range.