RESUMO
Ultraviolet (UV) irradiation induces detrimental changes in human skin which result in photoaging. UV-induced intracellular changes cause degradation of extracellular matrix (ECM). UV-stimulated cleavage of collagen in ECM occurs via matrix metalloproteinases (MMPs). (±)-syringaresinol (SYR), a phytochemical which belongs to the lignan group of polyphenols, was investigated for its ability to reverse the UVA-induced changes in human HaCaT keratinocytes and dermal fibroblasts (HDFs) in vitro. Effect of SYR on UVA-induced changes was investigated by production and activation of MMPs and its transcriptional upstream effectors; mitogen-activated protein kinases (MAPKs) and pro-inflammatory mediators. Levels of expression were determined using ELISA, RT-PCR and immunoblotting. UVA irradiation stimulated the production of MMP-1 and inhibited collagen production. SYR treatment suppressed MMP-1 and enhanced collagen production in UVA-irradiated HaCaT keratinocytes and HDFs. SYR repressed the UV-induced phosphorylation of p38, ERK and JNK MAPKs in HaCaT keratinocytes while only suppressing JNK phosphorylation in HDFs. In addition, SYR was able to inhibit UVA-induced production of inflammatory cytokines; TNF-α, COX-2, IL-1ß and IL-6. Moreover, SYR suppressed the activator protein-1 (AP-1), a heterodimer of phosphorylated transcription factors c-Jun and c-Fos. SYR-treatment decreased nuclear levels of activated c-Fos and c-Jun as a mechanism to inhibit UVA-induced transcriptional activities leading to MMP-1 production. In conclusion, current results demonstrated that SYR could inhibit UVA-induced upregulation of MMP-1 by suppressing MAPK/AP-1 signaling in HaCaT keratinocytes and HDFs. Therefore, SYR was suggested as a potential compound with antiphotoaging properties against UVA-induced skin aging.
Assuntos
Fibroblastos/efeitos dos fármacos , Furanos/farmacologia , Queratinócitos/efeitos dos fármacos , Lignanas/farmacologia , Sistema de Sinalização das MAP Quinases , Metaloproteinase 1 da Matriz/metabolismo , Fator de Transcrição AP-1/metabolismo , Raios Ultravioleta , Colágeno/metabolismo , Ensaio de Imunoadsorção Enzimática , Fibroblastos/efeitos da radiação , Células HaCaT , Humanos , Inflamação , Queratinócitos/efeitos da radiação , Lignanas/metabolismo , Fosforilação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Envelhecimento da Pele , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Numerous medications are used to treat hyperpigmentation. However, several reports have indicated that repeated application of some agents, such as rhododendrol (RD), raspberry ketone (RK) and monobenzone (MB), can be toxic to melanocytes. Although these agents had severe side effects in human trials, no current in vitro methods can predict the safety of such drugs. This study assessed the in vitro effects of five depigmentary compounds including leukoderma-inducing agents. In particular, we determined the effects of different concentrations and exposure times of different depigmentary agents on cell viability and melanogenesis in the presence and absence of ultraviolet B (UVB) radiation. Concentrations of RD, RK and MB that inhibit melanogenesis are similar to concentrations that are cytotoxic; however, concentrations of rucinol (RC) and AP736 that inhibit melanogenesis are much lower than concentrations that are cytotoxic. Furthermore, the concentrations that cause toxic effects depend on exposure duration, and prolonged exposure to RD, RK and MB had more cytotoxic effects than prolonged exposure to RC and AP736. The cytotoxic effects of RD and RK appear to be mediated by apoptosis due to increased expression of caspase-3 and caspase-8; UVB radiation increased the cytotoxicity of these agents and also increased caspase activity. Our results indicate that different leukoderma-inducing compounds have different effects on the viability of normal epidermal melanocytes and suggest that the in vitro assay used here can be used to predict whether an investigational compound that induces leukoderma may lead to adverse effects in human trials.
Assuntos
Adamantano/análogos & derivados , Benzamidas/química , Butanóis/química , Butanonas/química , Epiderme/efeitos dos fármacos , Hidroquinonas/química , Melanócitos/efeitos dos fármacos , Pigmentação , Resorcinóis/química , Adamantano/química , Apoptose , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Epiderme/metabolismo , Humanos , Melaninas/biossíntese , Melanócitos/metabolismo , Necrose , Raios UltravioletaRESUMO
3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were studied as a novel class of inhibitors of tumor necrosis factor α (TNF-α) with regard to synthesis and in vitro SAR inhibition of TNF-α. The in vitro IC50 values of these compounds in rat and human peripheral blood mononuclear cells were at the sub-micromolar level.
Assuntos
Ciclopentanos/química , Ciclopentanos/farmacologia , Oximas/química , Oximas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Humanos , Leucócitos Mononucleares/química , Leucócitos Mononucleares/metabolismo , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety were performed to understand the mechanism of action and structure-activity relationship of these compounds. Contour map analysis indicated that steric contributions of the adamantyl moiety and electrostatic contributions of the hydroxyl group at the 3-position are important in the activity. Activities of the training set and test sets predicted by CoMFA fit well with actual activities, demonstrating that CoMFA, along with the best calculated q(2) value, has the best predictive ability.
Assuntos
Benzamidas/química , Melaninas/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melanócitos/fisiologia , Camundongos , Estrutura Secundária de ProteínaRESUMO
AP736 was identified as an antimelanogenic drug that can be used for the prevention of melasma, freckles, and dark spots in skin by acting as a suppressor of melanin synthesis and tyrosinase expression. Since macrophage-mediated inflammatory responses are critical for skin health, here we investigated the potential anti-inflammatory activity of AP736. The effects of AP736 on various inflammatory events such as nitric oxide (NO)/prostaglandin (PG) E2 production, inflammatory gene expression, phagocytic uptake, and morphological changes were examined in RAW264.7 cells. AP736 was found to strongly inhibit the production of both NO and PGE2 in lipopolysaccharide- (LPS-) treated RAW264.7 cells. In addition, AP736 strongly inhibited both LPS-induced morphological changes and FITC-dextran-induced phagocytic uptake. Furthermore, AP736 also downregulated the expression of multiple inflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase- (COX-) 2, and interleukin- (IL-) 1ß in LPS-treated RAW264.7 cells. Transcription factor analysis, including upstream signalling events, revealed that both NF-κB and AP-1 were targeted by AP736 via inhibition of the IKK/IκBα and IRAK1/TAK1 pathways. Therefore, our results strongly suggest that AP736 is a potential anti-inflammatory drug due to its suppression of NF-κB-IKK/IκBα and AP-1-IRAK1/TAK1 signalling, which may make AP736 useful for the treatment of macrophage-mediated skin inflammation.
Assuntos
Adamantano/análogos & derivados , Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , NF-kappa B/antagonistas & inibidores , Fator de Transcrição AP-1/antagonistas & inibidores , Adamantano/química , Adamantano/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Benzamidas/química , Linhagem Celular , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Interleucina-1beta/genética , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Melaninas/biossíntese , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pigmentação da Pele/efeitos dos fármacosRESUMO
Hyper-pigmentation causes skin darkness and medical disorders, such as post-inflammatory melanoderma and melasma. Therefore, the development of anti-melanogenic agents is important for treating these conditions and for cosmetic production. In our previous paper, we demonstrated that the anti-diabetic drug voglibose, a valiolamine derivative, is a potent anti-melanogenic agent. In addition, we proposed an alternative screening strategy to identify valiolamine derivatives with high skin permeability that act as anti-melanogenic agents when applied topically. In this study, we synthesized several valiolamine derivatives with enhanced lipophilicity and examined their inhibitory effects in a human skin model. N-(2-hydroxycyclohexyl)valiolamine (HV) possesses a stronger inhibitory effect on melanin production than voglibose in a human skin model, suggesting that HV is a more potent anti-melanogenic agent for the skin.
Assuntos
Cicloexanóis/farmacologia , Inositol/análogos & derivados , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Células Cultivadas , Cicloexanóis/síntese química , Humanos , Inositol/síntese química , Inositol/química , Inositol/farmacologia , Melanócitos/metabolismo , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismoRESUMO
Melanogenesis is essential for the protection of skin against UV, but excessive production of melanin causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we found that a tyrosinase inhibitor, AP736 (5-adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzamide) potently suppresses tyrosinase expression, and the mechanism underlying was elucidated. AP736 attenuated the melanin production induced by diverse melanogenic stimuli in murine and human melanocytes. It suppressed the expression of key melanogenic enzymes; tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. The expression of microphthalmia-associated transcription factor (MiTF), a major promoter of melanogenesis was also decreased. AP736 inhibited the activation of cAMP response element-binding protein (CREB) and phosphokinase A (PKA), and cAMP elevation, reflecting that cAMP-PKA-CREB signalling axis was suppressed, resulting in the downregulation of MiTF and tyrosinase. Along with the previously reported tyrosinase inhibitory activity, the suppression of cAMP-PKA-CREB-mediated MiTF and tyrosinase expression by AP736 may be efficient for the treatment for hyperpigmentation.
Assuntos
Adamantano/análogos & derivados , Benzamidas/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Fator de Transcrição Associado à Microftalmia/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Adamantano/química , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Humanos , Hiperpigmentação/metabolismo , Melaninas/química , Melanócitos/citologia , Melanoma Experimental/metabolismo , Camundongos , Transdução de Sinais , Pele/patologia , Neoplasias Cutâneas/metabolismoAssuntos
Adamantano/análogos & derivados , Benzamidas/farmacologia , Melanócitos/efeitos dos fármacos , MicroRNAs/metabolismo , Preparações Clareadoras de Pele/farmacologia , Adamantano/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Metaloproteinases da Matriz/metabolismo , Melaninas/antagonistas & inibidores , Melaninas/biossíntese , Melanócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento da Pele/efeitos dos fármacosRESUMO
A new series of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety has been synthesized, and the depigmenting and tyrosinase inhibitory activities of the molecules were evaluated. The lipophilic character of the adamantyl moiety appeared to confer greater depigmentation power on the benzamide derivatives as compared to those lacking adamantyl substitution. Molecular modeling was applied in order to elucidate the interactions between ligands and tyrosinase that led to inhibition.
Assuntos
Adamantano/análogos & derivados , Adamantano/farmacologia , Agaricales/enzimologia , Benzamidas/química , Benzamidas/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pigmentação da Pele/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Melaninas/antagonistas & inibidores , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Camundongos , Modelos Moleculares , Monofenol Mono-Oxigenase/metabolismoRESUMO
We synthesized benzoate ester derivatives of kojic acid with and without adamantane moiety. Benzoate derivatives 2a-e that did not contain an adamantane moiety showed potent tyrosinase inhibitory activities. However, depigmenting activity was not noted in a cell-based assay. Contrasting results were obtained for benzoate derivatives (3a-e) containing an adamantane moiety. Compounds 3a-e showed potent depigmenting activities without tyrosinase inhibitory activities. To the best of our knowledge, this is the first study showing the depigmenting activities of kojic acid derivatives without tyrosinase inhibitory activities.
Assuntos
Adamantano/química , Melaninas/antagonistas & inibidores , Melanócitos/efeitos dos fármacos , Pigmentação/efeitos dos fármacos , Pironas/química , Agaricales/enzimologia , Animais , Bioensaio , Sobrevivência Celular/efeitos dos fármacos , Ésteres , Melaninas/biossíntese , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Pironas/farmacologia , Relação Estrutura-Atividade , Tirosina/metabolismoRESUMO
A novel kojic acid derivative containing a trolox moiety, (±)-5-hydroxy-4-oxo-4H-pyran-2-yl methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate (3a), was synthesized. The two biologically active compounds, namely, kojic acid and trolox, were conjugated via an ester bond as they are expected to behave synergistically. The antioxidant activity and the tyrosinase inhibitory activity of this novel kojic acid derivative on melanogenesis were evaluated. Compound 3a exhibited potent tyrosinase inhibitory activity and radical scavenging activity. Limited structure-activity relationship (SAR) investigations indicated that the tyrosinase inhibitory activities may originate from the kojic acid moiety, and the radical scavenging activity may be due to the phenolic hydroxyl group of trolox. Compound 3a also exhibited potent depigmenting activity in a cell-based assay. The limited SAR investigations revealed that the depigmenting activity of 3a may be due to the synergistic activities of kojic acid and its trolox moiety.
Assuntos
Benzopiranos/química , Cromanos/química , Sequestradores de Radicais Livres/farmacologia , Melanócitos/efeitos dos fármacos , Monofenol Mono-Oxigenase/metabolismo , Pironas/química , Pironas/farmacologia , Animais , Benzopiranos/síntese química , Benzopiranos/farmacologia , Sítios de Ligação , Diferenciação Celular , Simulação por Computador , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Melanócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pironas/síntese química , Relação Estrutura-AtividadeRESUMO
AP736 itself is a novel skin whitening agent reported to exhibit anti-melanogenic and tyrosinase inhibitory activity. However, formulating a topical product has been difficult because AP736 is insoluble in water as well as in many oils. In this study, we aimed to develop a new topical delivery system in which AP736 is not only physically stable, but also suitably delivered to the skin. By calculating each HSP (Hansen Solubility Parameters), ethylenedioxy moiety-containing compounds could be easily selected for the formulation ingredients of AP736. Although diethylene glycol monoethyl ether with the highest solubility of AP736 enalbes to make AP736-incorporated water-in-oil emulsions well, the recrystallization of AP736 was observed in oil-in-water emulsions. Therefore, we fabricated polymeric nanoparticles (PNPs) in order to encapsulate AP736 to prevent its recrystallization. We used three different PEG-PCL polymers with various chain lengths and ethylenedioxy moiety-containing surfactants (i.e. Choleth) for fabricating PNPs. The prepared PNPs had a mean particle size from 50â¯nm to 200â¯nm. Most of PNPs showed the good encapsulation efficiency up to 90%. In particular, Choleth-24 had a significant role in encapsulating AP736 in PNPs. After encapsulation of AP736, no significant changes were observed in the sizes of tested PNPs within 4â¯weeks. Further, the recrystallization of AP736 was not observed in oil-in-water emulsions after 24â¯weeks of storage at 40⯰C. In vitro permeation study using Strat-M showed that PNPs containing Choleth-24 has the faster release pattern compared to PNPs using Tween 80 and saturated in D.I. water. These results are demonstrating that PNPs might be an effective vehicle for stabilization in oil-in-water emulsions and topical application of AP736.
Assuntos
Adamantano/análogos & derivados , Benzamidas/administração & dosagem , Portadores de Fármacos/administração & dosagem , Lactonas/administração & dosagem , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Preparações Clareadoras de Pele/administração & dosagem , Adamantano/administração & dosagem , Adamantano/química , Benzamidas/química , Portadores de Fármacos/química , Lactonas/química , Nanopartículas/química , Polietilenoglicóis/química , Pele/metabolismo , Absorção Cutânea , Preparações Clareadoras de Pele/química , SolubilidadeRESUMO
BACKGROUND/PURPOSE: AP736 is a novel compound with an adamantyl benzylbenzamide moiety that has shown antimelanogenic activity in melanocytes in vitro and in artificial skin equivalent through the inhibition of key melanogenic enzymes and suppression of the cAMP-phosphokinase A-cAMP response element-binding protein signaling pathway. To estimate the clinical effectiveness of AP736 for the treatment of facial hyperpigmentation, we examined the efficacy and safety of a topical formulation containing AP736 compared with a vehicle formulation in human facial skin. To evaluate the degree of whitening when used in a real-life situation, subjects with hyperpigmentation conditions were selected and the trial was performed from mid-May to the end of June, when there are strong UV rays in Korea. MATERIALS AND METHODS: Forty-eight healthy Korean women aged 20-60 years were enrolled in this study for 6 weeks. Women who were pregnant or undergoing any concurrent therapy were excluded. Subjects were instructed to apply a randomly assigned formulation containing 0.5% AP736 (test formulation; n = 24) or vehicle (vehicle control; n = 24) in addition to an assigned sunscreen with a twice-daily application protocol. The degree of facial pigmentation was measured objectively using a Mexameter MX18 and Chromameter CM700, in addition to assessment by physicians using clinical photographs. RESULTS: The AP736 formulation was significantly (P < 0.05) more effective than the vehicle control formation in reducing the appearance of pigmentation at 3- and 6-week follow-up visits. CONCLUSION: A formulation containing a novel skin whitening ingredient, AP736, effectively reduced pigmentation and was well tolerated by study subjects in summer season.
Assuntos
Adamantano/análogos & derivados , Benzamidas/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Dermatoses Faciais/tratamento farmacológico , Hiperpigmentação/tratamento farmacológico , Adamantano/administração & dosagem , Adamantano/uso terapêutico , Administração Cutânea , Adulto , Benzamidas/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Estações do Ano , Protetores Solares/administração & dosagem , Adulto JovemRESUMO
Recently, 1,3-diarylalkyl thioureas have merged as one of the promising nonvanilloid TRPV1 antagonists possessing excellent therapeutic potential in pain regulation. In this paper, the full structure-activity relationship for TRPV1 antagonism of a novel series of 1,3-diarylalky thioureas is reported. Exploration of the structure-activity relationship, by systemically modulating three essential pharmacophoric regions, led to six examples of 1,3-dibenzyl thioureas, which exhibit Ca(2+) uptake inhibition in rat DRG neuron with IC(50) between 10 and 100 nM.
Assuntos
Canais Iônicos/antagonistas & inibidores , Tioureia/análogos & derivados , Tioureia/síntese química , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Gânglios Espinais/citologia , Técnicas In Vitro , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Canais de Cátion TRPV , Tioureia/farmacologiaRESUMO
Recently, much effort has been made to develop effective dermatological depigmenting compounds. In this study, we investigated the novel candidate compound, AP736 (an adamantyl benzylbenzamide derivative), and its effects on melanogenesis in B16F10 melanoma cells, as well as the mechanisms involved. AP736 has been reported to exert anti-melanogenic effects in melanocytes in vitro and in artificial skin equivalents through the inhibition of key melanogenic enzymes and the suppression of the cAMP-protein kinase A (PKA)-cAMP response elementbinding protein (CREB) signaling pathway. Thus, we examined another pathway of melanogenesis involving the effects of AP736 on the glycogen synthesis kinase 3ß (GSK3ß) pathway. Melanin content and tyrosinase activity were measured using a spectrophotometer after the cells were treated with AP736. The AP736-induced activation of signaling pathways was examined by western blot analysis. We confirmed that AP736 decreased melanin production in a dose-dependent manner; however, it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme. The expression of microphthalmia-associated transcription factor, tyrosinase, and related signal transduction pathways was also investigated. The Wnt signaling pathway is deeply involved in melanogenesis; therefore, phosphorylation by GSK3ß was assessed following treatment with AP736. AP736 induced GSK3ß phosphorylation (inactivation), but it did not alter the level of ß-catenin. Furthermore, the expression of α-melanocyte-stimulating hormone-induced tyrosinase was downregulated by AP736. Our data suggest that AP736 exerts hypopigmentary effects through the downregulation of tyrosinase via GSK3ß phosphorylation.
Assuntos
Adamantano/análogos & derivados , Benzamidas/farmacologia , Carcinogênese/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Melanoma Experimental/diagnóstico , Fosforilação/efeitos dos fármacos , Adamantano/farmacologia , Animais , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanoma Experimental/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC(50)=31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC(50)=31 nM), showed 5-fold higher antagonistic activity than 1 in (45)Ca(2+)-influx assay.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Canais Iônicos/antagonistas & inibidores , Animais , Sinalização do Cálcio/efeitos dos fármacos , Gânglios Espinais/citologia , Concentração Inibidora 50 , Canais Iônicos/agonistas , Ligantes , Neurônios , Ratos , Receptores de Droga/antagonistas & inibidores , Relação Estrutura-Atividade , Canais de Cátion TRPVRESUMO
An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-diarylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the 'hard soft acid base' principle. The reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones.
Assuntos
Furanos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Inibidores de Ciclo-Oxigenase/síntese química , CetonasRESUMO
A series of N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butylbenzyl thioureas were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor in rat DRG neurons. Their structure-activity relationship reveals that there is a space for another hydrophobic binding interaction around 2-position in 4-tert-butylbenzyl region. Among the prepared derivatives, 6n show the highest antagonistic activity against the vanilloid receptor (IC(50)=15 nM).
Assuntos
Receptores de Droga/antagonistas & inibidores , Sulfonamidas/química , Tioureia/química , Animais , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Ligantes , Ratos , Receptores de Droga/metabolismo , Sulfonamidas/metabolismo , Tioureia/metabolismoRESUMO
A series of chain-branched 1,3-dibenzylthiourea derivatives were synthesized, and tested their antagonist activity against vanilloid receptor 1. Chain-branching led to a significant change in the mode of action and the potency. (R)-Methyl or ethyl-branched 1,3-dibenzylthiourea derivatives showed the most potent antagonist activity up to the IC(50) value of 0.05 microM which is 10-fold more potent than capsazepine.
Assuntos
Receptores de Droga/antagonistas & inibidores , Tioureia/química , Animais , Células Cultivadas , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Ratos , Receptores de Droga/metabolismo , Tioureia/metabolismo , Tioureia/farmacologiaRESUMO
A novel non-vanilloid VR1 antagonist consisting of a new vanilloid equivalent exhibits excellent analgesic effects as well as highly potent antagonistic activities in both capsaicin single channel and calcium uptake assays. In addition, the structural requirement for the vanilloid equivalent of the potent VR1 antagonist has also been elucidated.