RESUMO
Loxosceles spiders' venoms consist of a mixture of proteins, including the sphingomyelinases D (SMases D), which are the main toxic components responsible for local and systemic effects in human envenomation. Herein, based on the structural information of SMase D from Loxosceles laeta spider venom and virtual docking-based screening approach, three benzene sulphonate compounds (named 1, 5 and 6) were identified as potential Loxosceles SMase D inhibitors. All compounds inhibited the hydrolysis of the sphingomyelin substrate by both recombinant and native SMases D. Compounds 5 and 6 acted as SMases D uncompetitive inhibitors with Ki values of 0.49 µM and 0.59 µM, respectively. Compound 1 is a mixed type inhibitor, and presented a Ki value of 0.54 µM. In addition, the three compounds inhibited the binding of SMases D to human erythrocytes and the removal of glycophorin C from the cell surface, which are important events in the complement-dependent haemolysis induced by Loxosceles venom. Moreover, compounds 5 and 6 reduced the binding of SMases to human keratinocytes membrane and the venom induced cell death. Importantly, compounds 5 and 6 also controlled the development of the necrotic lesion in an in vivo model of loxoscelism. Together, our findings indicate that the novel SMase D inhibitors presented here are able to suppress both local and systemic reactions induced by Loxosceles venoms. Since the number of Loxosceles envenomation accidents is currently growing worldwide, our results indicate that both inhibitors are promising scaffolds for the rational design of new drugs targeting SMases D from these spiders.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Dermatopatias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Picada de Aranha/tratamento farmacológico , Animais , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Coelhos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , AranhasRESUMO
AIMS: Evaluate the effect of LASSBio-596, structurally designed as a new hybrid of thalidomide, on inflammatory corneal angiogenesis. METHODS: Eighteen rabbits were submitted to an alkaline cauterization in the right cornea. The animals were randomly allocated to three groups: vehicle, dexamethasone and LASSBio-596. Drugs were administered by eyedrops 3 times a day for 21 days. Evaluations were performed on days 3, 6, 9, 12, 15, 18 and 21 after cauterization. At these time points, digital images of the cornea were captured in a standard fashion. The angiogenic response was measured using software that was developed specifically for this purpose. It calculated the following parameters: neovascularization area (NA), total vascular length (TVL) and blood vessel number (BVN). RESULTS: It was observed that dexamethasone significantly decreased NA, TVL and BVN during all assessments. From the NA the angiogenesis rate (AR) was calculated in each group. Therefore, dexamethasone completely inhibited the inflammatory corneal angiogenesis with an AR of -0.001 ± 0.006 mm(2)/day, which was significantly lower (p < 0.001) than that observed after treatment with vehicle (0.078 ± 0.024 mm(2)/day) and LASSBio-596 (0.054 ± 0.012 mm(2)/day). Although LASSBio-596 reduced angiogenesis in relation to vehicle, according to NA, TVL and BVN values, this difference was not statistically significant. However, it was found that the AR as measured in the LASSBio-596 group was significantly lower (p < 0.05) than that seen in control animals, indicating a potential antiangiogenic effect. CONCLUSION: We conclude that topical application of LASSBio-596 at 1.0% has a potential inhibitory effect on inflammatory corneal angiogenesis in rabbits.
Assuntos
Neovascularização da Córnea/tratamento farmacológico , Ceratite/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Ftalimidas/uso terapêutico , Talidomida/química , Animais , Neovascularização da Córnea/diagnóstico , Dexametasona/farmacologia , Modelos Animais de Doenças , Glucocorticoides/farmacologia , Ceratite/diagnóstico , Masculino , Soluções Oftálmicas , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Ácidos Ftálicos , Ftalimidas/administração & dosagem , Ftalimidas/química , Coelhos , SulfonamidasRESUMO
LASSBio-985 is a sulfonamide compound designed as a simplified structure of a nonselective phosphodiesterase type 4 (PDE-4) inhibitor that promotes vasodilatory activity in vitro. PDE are enzymes responsible for the hydrolysis of cyclic adenosine 3',5'- monophosphate and cyclic guanosine 3',5'-monophosphate. Five different isozymes of PDE are found in vascular smooth muscle (PDE1-PDE5). Aortic rings, with or without endothelium, from male normotensive and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. Blood pressure was measured in Wistar Kyoto (WKY) rats and SHR during intravenous infusion of LASSBio-985 (10 mg/kg/min) during 15 min. LASSBio-985 induced a concentration-dependent vasodilation in aortic rings from normotensive and SHR, which was almost completely inhibited in endothelium-denuded vessels. Vasodilatory activity was also reduced in endothelium-intact aortic rings that had been pretreated with N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor and 1H-[1,2,4]oxadiazolod[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. LASSBio-985-induced vasodilation was also inhibited by sildenafil (100 µm) and SQ 22536, a PDE5 inhibitor and adenylate cyclase inhibitor, respectively. To evaluate the involvement of some endothelial receptors, atropine, diphenhydramine, HOE 140, naloxone, propranolol, indomethacin, and wortmannin were tested, but none inhibited the effects of LASSBio-985. The residual effect observed on endothelium-denuded aortic rings was abolished by nicardipine, a voltage-sensitive-Ca(2+)-channel blocker. Intravenous infusion of LASSBio-985 (10 mg/kg/min) significantly reduced systolic and diastolic pressures in both WKY and SHR. LASSBio-985 is a compound with vasodilatory activity, which could be consequent to PDE1 inhibition and voltage-sensitive-Ca(2+)-channel blockade.
Assuntos
Anti-Hipertensivos/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Sulfonamidas/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Aorta Torácica/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Técnicas In Vitro , Masculino , Estrutura Molecular , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/fisiopatologia , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacocinética , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Sulfonamidas/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Vasodilatadores/química , Vasodilatadores/farmacologiaRESUMO
A series of drug-like compounds derived from Sildenafil, Vardenafil and Tadalafil analogues were modelled through the MIA-QSAR (multivariate image analysis applied to quantitative structure-activity relationships) ligand-based approach. A highly predictive model was achieved and novel compounds, miscellany of substructures of these three representative phosphodiesterase type-5 (PDE-5) inhibitors were predicted using the calibration parameters obtained through partial least squares (PLS) regression. The high bioactivities of eight promising compounds were corroborated by docking evaluation. Calculated ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) profiles for such compounds suggest advantages of some of them over the currently available, most common drugs used for the treatment of erectile dysfunction.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Animais , Carbolinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Imidazóis/química , Camundongos , Modelos Moleculares , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/toxicidade , Piperazinas/química , Purinas/química , Relação Quantitativa Estrutura-Atividade , Ratos , Citrato de Sildenafila , Sulfonas/química , Tadalafila , Triazinas/química , Dicloridrato de VardenafilaRESUMO
We investigated the mechanisms of action of Gnaphalium liebmannii which is used as a folk medicine in México for treating various respiratory diseases such as gripe, fever, asthma, cough, cold, bronchitis, expectorating, and bronchial affections. The tension changes of guinea pig tracheal segments were isometrically recorder on a polygraph. Hexane extract of Gnaphalium liebmannii was the most active relaxant extract (IC(30)=54.23+/-19.79 microg/mL with 99.5+/-3.2 % of relaxation), followed by dichloromethane extract (IC(30)=120.22+/-5.27 microg/mL) and methanol extract (IC(30)=190.25+/-30.02 microg/mL). Hexane extract produced a parallel rightward shift of the concentration-response curve of carbachol in a competitive manner (pA(2)=-2.4), but did not modify the concentration-response curves for histamine. The relaxant effect of hexane extract of Gnaphalium liebmannii was unaffected by the presence of propranolol (3x10(-6)M) or glibenclamide (10 microM). However hexane extract produced a leftward shifts of the concentration-response curve of forskolin (10(-8) to 10(-3)M), nitroprusside (10(-10) to 10(-6)M), isoproterenol (3x10(-10) to 3x10(-5)M) and aminophylline (10(-11) to 10(-2)M). The above results suggest that Gnaphalium liebmannii induce relaxation of the tracheal muscle, probably via phosphodiesterase inhibition. The bronchodilator effect of Gnaphalium liebmannii might explain in part their traditional use as anti-asthmatic remedy.
Assuntos
Broncodilatadores/farmacologia , Gnaphalium , Hexanos/química , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Solventes/química , Traqueia/efeitos dos fármacos , Aminofilina/farmacologia , Animais , Broncodilatadores/química , Colforsina/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Metanol/química , Cloreto de Metileno/química , México , Nitroprussiato/farmacologia , Inibidores de Fosfodiesterase/química , Extratos Vegetais/farmacologiaRESUMO
The interaction of Ca(2+)-ions with sildenafil citrate (Viagra) leads to the precipitation of a new polymorph variety of sildenafil base. Under the same conditions, Mg(2+), Zn(2+), and Cd(2+) ions form structurally related crystalline complexes of the composition Me(2+)C(28)H(34)N(6)O(11)S. Lattice parameters have been determined showing that magnesium compound belongs to an orthorhombic system, while the zinc and cadmium compounds are its monoclinic distortions. All three compounds are thermally stable, undergoing decomposition above 175 degrees C with the consequent formation of carbonates Me(2+)CO(3) and oxides.
Assuntos
Metais/química , Piperazinas/química , Cátions Bivalentes , Inibidores de Fosfodiesterase/química , Purinas , Citrato de Sildenafila , Sulfonas , Vasodilatadores/químicaRESUMO
A series of isoxazolopyridazinones and analogues has been prepared and evaluated as Leishmania mexicana phosphodiesterase (PDE) inhibitors. Some of the synthesized compounds showed a moderate PDE inhibitory activity at 100 microM and preliminary structure-activity relationships were discussed.