RESUMO
Some new hemorphin-4 analogs with structures of Xxx-Pro-Trp-Thr-NH2 and Tyr-Yyy-Trp-Thr-NH2, where Xxx is 2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid or 2-amino-3-(4-dibenzylamino-2,6-dimethylphenyl)propanoic acid, and Yyy is (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2-Diphenyl-1-picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm-H4 and H4-P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6-Hz test compared to 67% activity of H4. Notably, only the H4-P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db-H4 and H4-P1 showed the most pronounced and long-lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm-H4 produced a dose-dependent thermal antinociception and H4-P2 inhibited only formalin-induced pain behavior.
Assuntos
Convulsões , Animais , Camundongos , Masculino , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade , Anticonvulsivantes/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Dor/tratamento farmacológico , Aminoácidos/química , Aminoácidos/farmacologia , Aminoácidos/síntese química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Analgésicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Relação Dose-Resposta a Droga , Modelos Animais de Doenças , Peptídeos Opioides/farmacologia , Peptídeos Opioides/síntese química , Peptídeos Opioides/química , Analgésicos Opioides/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/químicaRESUMO
Herein we present the biocatalysed preparation of a mono-N-carbamate-protected precursor of antitumoral Nutlin-3a through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with commercially available diallyl, diethyl and dimethyl carbonates. The reactions were conducted at different temperatures, for different reaction times and with variable co-solvent systems to evaluate the effects on the enzyme catalytic activity. The best results in terms of conversion, enantiomeric excess and yield were obtained when lipase from Candida antarctica B (CAL-B) was used with diallyl carbonate (DAC) when conducting the reaction solventless at 75 °C.
Assuntos
Lipase , Lipase/metabolismo , Lipase/química , Estereoisomerismo , Proteínas Fúngicas/metabolismo , Biocatálise , Piperazinas/química , Piperazinas/síntese química , Enzimas Imobilizadas/química , Solventes/química , Estrutura MolecularRESUMO
Various geraniol esters act as insect pheromones and display pharmacological activities, especially as neuroprotective agents. Therefore, the search for synthetic strategies alternative to traditional chemical synthesis could help designing ecofriendly routes for the preparation of such bioactive compounds. Hence, this work aims at the microwave-assisted enzymatic synthesis of geranyl esters in solvent-free systems. The process variables were optimized for the synthesis of geranyl acetoacetate, achieving 85% conversion after 60 min using a 1:5 substrates molar ratio (ester to geraniol), 80 °C and 8.4% of Lipozyme 435 lipase without removal of the co-produced methanol. On the other hand, a 95% conversion was reached after 30 min using 1:6 substrates molar ratio, 70 °C and 7% lipase in the presence of 5Å molecular sieves for the methanol capture. In addition, the lipase showed good reusability, maintaining the same activity for five reaction cycles. Finally, under the above optimized conditions, other geraniol esters were successfully synthetized such as the geranyl butyrate (98%), geranyl hexanoate (99%), geranyl octanoate (98%), and geranyl (R)-3-hydroxybutyrate (56%). These results demonstrate the microwave-assisted lipase-catalyzed transesterification in a solvent-free system as an excellent and sustainable catalytic methodology to produce geraniol esters.
RESUMO
Permeability transition pore (PTP) molecular composition and activity modulation have been a matter of research for several years, especially due to their importance in ischemia reperfusion injury (IRI). Notably, c subunit of ATP synthase (Csub) has been identified as one of the PTP-forming proteins and as a target for cardioprotection. Oligomycin A is a well-known Csub interactor that has been chemically modified in-depth for proposed new pharmacological approaches against cardiac reperfusion injury. Indeed, by taking advantage of its scaffold and through focused chemical improvements, innovative Csub-dependent PTP inhibitors (1,3,8-Triazaspiro[4.5]decane) have been synthetized in the past. Interestingly, four critical amino acids have been found to be involved in Oligomycin A-Csub binding in yeast. However, their position on the human sequence is unknown, as is their function in PTP inhibition. The aims of this study are to (i) identify for the first time the topologically equivalent residues in the human Csub sequence; (ii) provide their in vitro validation in Oligomycin A-mediated PTP inhibition and (iii) understand their relevance in the binding of 1,3,8-Triazaspiro[4.5]decane small molecules, as Oligomycin A derivatives, in order to provide insights into Csub interactions. Notably, in this study we demonstrated that 1,3,8-Triazaspiro[4.5]decane derivatives inhibit permeability transition pores through a FO-ATP synthase c subunit Glu119-independent mechanism that prevents Oligomycin A-related side effects.
Assuntos
Proteínas de Transporte da Membrana Mitocondrial , ATPases Mitocondriais Próton-Translocadoras , Humanos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Trifosfato de Adenosina/metabolismo , PermeabilidadeRESUMO
The synthesis of a small library of NH-Boc- or NH-Fmoc-protected l-phenylalanines carrying methyl groups at positions 2 and 6 and diverse functionalities at position 4 has been achieved. The approach, which took advantage of a Pd-catalyzed directed C-H dimethylation of picolinamide derivatives, allowed the electronic and steric properties of the resulting amino acid derivatives to be altered by appending a variety of electron-withdrawing, electron-donating, or bulky groups.
Assuntos
Aminoácidos , Fenilalanina , Aminoácidos/química , Fenilalanina/química , Tirosina/análogos & derivadosRESUMO
Maintaining a high percentage of living and functional cells in those pathologies in which excessive cell death occurs, such as neurodegenerative disorders and cardiovascular diseases, is one of the most intriguing challenges in the field of biochemical research for drug discovery. Here, mitochondrial permeability transition-driven regulated cell death is the main mechanism of mitochondrial impairment and cell fate; this pathway is still lacking of satisfying pharmacological treatments to counteract its becoming; for this reason, it needs continuous and intense research to find new compounds as modulator of the permeability transition pore complex (PTPC) activity. In this study, we report the identification of small-molecule urea derivatives able to inhibit PTPC opening following calcium overload and selected for future use in cytoprotection.
Assuntos
Proteínas de Transporte da Membrana Mitocondrial , Ureia , Trifosfato de Adenosina/metabolismo , Azirinas , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/química , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fosfatidilcolinas , Ureia/metabolismo , Ureia/farmacologiaRESUMO
An increased awareness of diseases associated with Human herpesvirus 6 (HHV-6) infection or reactivation has resulted in a growing interest in the evaluation of the best treatment options available for the clinical management of HHV-6 disease. However, no compound has yet been approved exclusively for HHV-6 infection treatment. For this reason, the identification of anti-HHV6 compounds provides a valuable opportunity for developing efficient antiviral therapies. A possible target for antiviral drugs is the virus-cell fusion step. In this study, we synthetized potential fusion intermediates inhibitors based on the rhodanine structure. The obtained derivatives were tested for cytotoxicity and for antiviral activity in human cells infected with HHV6. Level of infection was monitored by viral DNA quantification at different time points up to 7 days post infection. Among the synthetized derivatives, 9e showed a significative inhibitory effect on viral replication that lasted over 7 days, probably attributable to the particular combination of hydrophilic and hydrophobic substituents to the rhodanine moiety. Our results support the use of these amphipathic fusion inhibitors for the treatment of HHV-6 infections.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 6/efeitos dos fármacos , Rodanina/farmacologia , Infecções por Roseolovirus/tratamento farmacológico , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Rodanina/síntese química , Rodanina/química , Infecções por Roseolovirus/virologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Biocatalyzed synthesis can be exploited to produce high-value products, such as prodrugs. The replacement of chemical approaches with biocatalytic processes is advantageous in terms of environmental prevention, embracing the principles of green chemistry. In this work, we propose the covalent attachment of xylitol to ibuprofen to produce an IBU-xylitol ester prodrug. Xylitol was chosen as a hydrophilizer for the final prodrug, enhancing the water solubility of ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) extensively used as an analgesic, anti-inflammatory, and antipyretic. Despite being the third-most-prescribed medicine in the world, the aqueous solubility of ibuprofen is just 21 mg/L. This poor water solubility greatly limits the bioavailability of ibuprofen. We aimed to functionalize ibuprofen with xylitol using the reusable immobilized N435 biocatalyst. Instead of a biphasic media, we proposed a monophasic reaction environment. The characterization of the IBU-xylitol ester was performed by 1H, 13C-NMR, DEPT, COSY, HMQC, HMBC, FTIR, and MS spectroscopy. Preliminary in vitro tests showed that this enzymatically synthesized prodrug of ibuprofen reduced the expression of the interleukin 8 genes in human bronchial epithelial cells (IB3-1) from cystic fibrosis (CF) patients.
Assuntos
Ibuprofeno/química , Pró-Fármacos/química , Xilitol/química , Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Biocatálise , Disponibilidade Biológica , Linhagem Celular , Fibrose Cística/tratamento farmacológico , Ésteres/química , Humanos , Ibuprofeno/farmacologia , Pró-Fármacos/farmacologia , Solubilidade , Água/químicaRESUMO
Plant-derived remedies rich in chalcone-based compounds have been known for centuries in the treatment of specific diseases, and nowadays, the fascinating chalcone framework is considered a useful and, above all, abundant natural chemotype. Velutone F, a new chalconoid from Millettia velutina, exhibits a potent effect as an NLRP3-inflammasome inhibitor; the search for new natural/non-natural lead compounds as NLRP3 inhibitors is a current topical subject in medicinal chemistry. The details of our work toward the synthesis of velutone F and the unknown non-natural regioisomers are herein reported. We used different synthetic strategies both for the construction of the distinctive benzofuran nucleus (BF) and for the key phenylpropenone system (PhP). Importantly, we have disclosed a facile entry to the velutone F via synthetic routes that can also be useful for preparing non-natural analogs, a prerequisite for extensive SAR studies on the new flavonoid class of NLRP3-inhibitors.
Assuntos
Chalconas , Inflamassomos , Chalconas/farmacologia , Flavonoides/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
BACKGROUND: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and µ receptors produces analgesia with reduced side effects in nonhuman primates. METHODS: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with µ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. RESULTS: Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] µg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] µg/kg). Pretreatment with antagonists selective for nociceptin and µ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 µg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 µg; 3,009 ± 1,474 scratches). CONCLUSIONS: In nonhuman primates, the µ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/µ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.
Assuntos
Indóis/administração & dosagem , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Receptores Opioides/agonistas , Compostos de Espiro/administração & dosagem , Analgésicos Opioides/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Fentanila/administração & dosagem , Injeções Espinhais , Macaca mulatta , Masculino , Peptídeos Opioides/administração & dosagem , Receptores Opioides/fisiologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/fisiologia , Receptor de Nociceptina , NociceptinaRESUMO
4,4'-Dimethylaminorex (4,4'-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1-60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4'-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers' co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.
Assuntos
Comportamento Animal/efeitos dos fármacos , Oxazóis/toxicidade , Transtornos Psicofisiológicos/metabolismo , Transtornos Psicofisiológicos/patologia , Psicotrópicos/toxicidade , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxazóis/classificação , Oxazóis/urina , Transtornos Psicofisiológicos/induzido quimicamente , Psicotrópicos/classificação , Psicotrópicos/urina , EstereoisomerismoRESUMO
Bile acids (BAs) are a family of steroids synthesized from cholesterol in the liver. Among bile acids, ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. The clinical effectiveness of UDCA includes its choleretic activity, the capability to inhibit hydrophobic bile acid absorption by the intestine under cholestatic conditions, reducing cholangiocyte injury, stimulation of impaired biliary output, and inhibition of hepatocyte apoptosis. Despite its clinical effectiveness, UDCA is poorly soluble in the gastro-duodeno-jejunal contents, and pharmacological doses of UDCA are not readily soluble in the stomach and intestine, resulting in incomplete absorption. Indeed, the solubility of 20 mg/L greatly limits the bioavailability of UDCA. Since the bioavailability of drug products plays a critical role in the design of oral administration dosages, we investigated the enzymatic esterification of UDCA as a strategy of hydrophilization. Therefore, we decided to enzymatically synthesize a glyceric ester of UDCA bile acid to produce a more water-soluble molecule. The esterification reactions between UDCA and glycerol were performed with an immobilized lipase B from Candida antarctica (Novozym 435) in solvent-free and solvent-assisted systems. The characterization of the UDCA-monoglyceride, enzymatically synthesized, has been performed by 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, IR, and MS spectroscopy.
Assuntos
Enzimas Imobilizadas/química , Proteínas Fúngicas/química , Monoglicerídeos/química , Pró-Fármacos/síntese química , Ácido Ursodesoxicólico/química , Basidiomycota/enzimologia , Catálise , Cromatografia Líquida de Alta Pressão , Estabilidade Enzimática , Enzimas Imobilizadas/metabolismo , Esterificação , Proteínas Fúngicas/metabolismo , Glicerol/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Solubilidade , Solventes/química , TemperaturaRESUMO
In recent decades liposomes have been used in different field thanks to their ability to act as a vehicle for a wide range of biomolecules, their great versatility and their easy production. The aim of this study was to evaluate liposomes as a vehicle for the actives present in the HelixComplex (HC) snail mucus for topical delivery. Liposomes composed of a mixture of phosphatidylcholine, cholesterol and octadecylamine were prepared with and without HC (empty liposomes) and their biological efficacy was tested by evaluating cell viability and migration. HC-loaded liposomes (LHC) were stable throughout 60 days of observation, and showed interesting effects on wound healing reconstitution. In particular, we observed that 25 µg/mL LHC were already able to induce a higher cell monolayer reconstitution in comparison to the untreated samples and HC treated samples after only 4 h (28% versus 10% and 7%, p = 0.03 and p= 0.003, respectively). The effect was more evident at 24 h in comparison with the untreated control (54% versus 21.2% and 41.6%, p = 0.006 and p = NS, respectively). These results represent a preliminary, but promising, novelty in the delivery strategy of the actives present in the HelixComplex mucus.
Assuntos
Muco/química , Caramujos/química , Animais , Morte Celular , Linhagem Celular , Fibroblastos/citologia , Técnica de Fratura por Congelamento , Humanos , Lipídeos/análise , Lipossomos/ultraestrutura , Espectrofotometria Infravermelho , Cicatrização/efeitos dos fármacosRESUMO
Methiopropamine is a structural analog of methamphetamine that is categorized as a novel psychoactive substance. It primarily acts as a norepinephrine-dopamine reuptake inhibitor and, secondarily, as a serotonin reuptake inhibitor. In humans, methiopropamine induces stimulation and alertness and increases focus and energy. However, significant side effects are reported, such as tachycardia, anxiety, panic attacks, perspiration, headache, and difficulty in breathing. To date, little data is available regarding its pharmacodynamic effects, thereby we aimed to investigate the acute in vivo effects induced by this drug on sensorimotor responses, body temperature, pain thresholds, motor activity, and cardiovascular and respiratory systems in CD-1 male mice. We selected a range of doses that correspond to the whole range of human reported use, in order to evaluate the threshold of adverse effects presentation. This study demonstrates that methiopropamine acts as a dopaminergic and noradrenergic stimulating drug and that the highest doses (10-30 mg/kg) impair the visual placing response, facilitate the acoustic and tactile response, induce hypothermia, increase mechanical and thermal analgesia, stimulate locomotor activity, induce motor stereotypies, and strongly affected cardiovascular and respiratory parameters, increasing heart rate, breath rate, and blood pressure but reducing oxygen saturation. On the contrary, lower doses do not show any of those effects. We hypothesize that there is a range of doses that do enhance performance but do not seem hazardous to users: this gap could induce the perception of safety and increase the abuser population.
Assuntos
Metanfetamina/análogos & derivados , Tiofenos/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Psicotrópicos/farmacologiaRESUMO
The screening of chemical libraries based on cellular biosensors is a useful approach to identify new hits for novel therapeutic targets involved in rare genetic pathologies, such as ß-thalassemia and sickle cell disease. In particular, pharmacologically mediated stimulation of human γ-globin gene expression, and increase of fetal hemoglobin (HbF) production, have been suggested as potential therapeutic strategies for these hemoglobinopathies. In this article, we screened a small chemical library, constituted of 150 compounds, using the cellular biosensor K562.GR, carrying enhanced green fluorescence protein (EGFP) and red fluorescence protein (RFP) genes under the control of the human γ-globin and ß-globin gene promoters, respectively. Then the identified compounds were analyzed as HbF inducers on primary cell cultures, obtained from ß-thalassemia patients, confirming their activity as HbF inducers, and suggesting these molecules as lead compounds for further chemical and biological investigations.
Assuntos
Anemia Falciforme/sangue , Descoberta de Drogas/métodos , Hemoglobina Fetal/biossíntese , Biossíntese de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Talassemia beta/sangue , Anemia Falciforme/tratamento farmacológico , Técnicas Biossensoriais/métodos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Humanos , Células K562 , Proteínas Luminescentes/genética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Globinas beta/genética , Talassemia beta/tratamento farmacológico , gama-Globinas/genética , Proteína Vermelha FluorescenteRESUMO
Biofilm production is regulated by the Quorum Sensing system. Nowadays, Quorum Sensing represents an appealing target to design new compounds to increase antibiotics effects and avoid development of antibiotics multiresistance. In this research the use of liposomes to target two novel synthetic biofilm inhibitors is presented, focusing on a preformulation study to select a liposome composition for in vitro test. Five different liposome (LP) formulations, composed of phosphatidyl choline, cholesterol and charged surfactant (2:1:1, molar ratio) have been prepared by direct hydration and extrusion. As charged surfactants dicetyl phosphate didecyldimethylammonium chloride, di isobutyl phenoxy ethyl dimethyl benzyl ammonium chloride and stearylamine (SA) and have been used. Liposome charge, size and morphology were investigated by zeta potential, photon correlation spectroscopy, small angle x-ray spectroscopy and electron microscopy. LP-SA was selected for the loading of biofilm inhibitors and subjected to high performance liquid chromatography for entrapment capacity evaluation. LP-SA loaded inhibitors showed a higher diameter (223.6 nm) as compared to unloaded ones (205.7 nm) and a dose-dependent anti-biofilm effect mainly after 48 h of treatment, while free biofilm inhibitors loose activity. In conclusion, our data supported the use of liposomes as a strategy to enhance biofilm inhibitors effect.
Assuntos
Antibacterianos/administração & dosagem , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Lipossomos/administração & dosagem , Nanopartículas/administração & dosagem , Percepção de Quorum , Antibacterianos/química , Lipossomos/química , Nanopartículas/químicaRESUMO
PEDOT (Poly(3,4-ethylenedioxythiophene)) is one of the most promising electrode materials for biomedical applications like neural recording and stimulation, thanks to its enhanced biocompatibility and electronic properties. Drug delivery by PEDOT is typically achieved by incorporating drugs as dopants during the electrodeposition procedure and a subsequent release can be promoted by applying a cathodic trigger that reduces PEDOT while enabling the drug to diffuse. This approach has several disadvantages including, for instance, the release of contaminants mainly due to PEDOT decomposition during electrochemical release. Herein we describe a new strategy based on the formation of a chemical linkage between the drug and the conductive polymer. In particular, dexamethasone was successfully integrated into a new electropolymerized PEDOT-Dex composite, leading to a self-adjusting drug release system based on a biochemically hydrolysable bond between dexamethasone and PEDOT.
RESUMO
Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and µ (δ-OR, κ-OR and µ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (â¼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and µ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.
Assuntos
Materiais Biomiméticos/química , Peptídeos Opioides/química , Piperidinas/química , Piperidinas/metabolismo , Receptores Opioides/química , Receptores Opioides/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Sítios de Ligação , Materiais Biomiméticos/metabolismo , Materiais Biomiméticos/farmacologia , Cristalografia por Raios X , Células HEK293 , Humanos , Ligantes , Modelos Moleculares , Antagonistas de Entorpecentes , Peptídeos Opioides/metabolismo , Peptídeos Opioides/farmacologia , Piperidinas/farmacologia , Conformação Proteica , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Compostos de Espiro/farmacologia , Especificidade por Substrato , Receptor de NociceptinaRESUMO
INTRODUCTION: Among novel psychoactive substances notified to EMCDDA and Europol were 1-cyclohexyl-x-methoxybenzene stereoisomers (ortho, meta, and para). These substances share some structural characteristics with phencyclidine and tramadol. Nowadays, no information on the pharmacological and toxicological effects evoked by 1-cyclohexyl-x-methoxybenzene are reported. The aim of this study was to investigate the effect evoked by each one stereoisomer on visual stimulation, body temperature, acute thermal pain, and motor activity in mice. METHODS: Mice were evaluated in behavioral tests carried out in a consecutive manner according to the following time scheme: observation of visual placing response, measures of core body temperature, determination of acute thermal pain, and stimulated motor activity. RESULTS: All three stereoisomers dose-dependent inhibit visual placing response (rank order: meta > ortho > para), induce hyperthermia at lower and hypothermia at higher doses (meta > ortho > para) and cause analgesia to thermal stimuli (para > meta = ortho), while they do not alter motor activity. CONCLUSIONS: For the first time, this study demonstrates that systemic administration of 1-cyclohexyl-x-methoxybenzene compounds markedly inhibit visual response, promote analgesia, and induce core temperature alterations in mice. This data, although obtained in animal model, suggest their possible hazard for human health (i.e., hyperthermia and sensorimotor alterations). In particular, these novel psychoactive substances may have a negative impact in many daily activities, greatly increasing the risk factors for workplace accidents and traffic injuries.
Assuntos
Anisóis/farmacologia , Temperatura Corporal/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Internet , Medição da Dor/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Animais , Anisóis/química , Anisóis/economia , Temperatura Corporal/fisiologia , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/economia , Humanos , Internet/economia , Masculino , Marketing/economia , Camundongos , Medição da Dor/métodos , Estereoisomerismo , Percepção Visual/fisiologiaRESUMO
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the ß1 and ß5 subunits of the proteasome with IC50 values in the sub-µm range.