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1.
Plant Dis ; 103(8): 1884-1888, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31161931

RESUMO

It is a common practice to add salicylhydroxamic acid (SHAM) into artificial medium in the in vitro sensitivity assay of fungal phytopathogens to the quinone outside inhibitor (QoI) fungicides. The rationale for adding SHAM is to inhibit fungal alternative oxidase, which is presumed to be inhibited by secondary metabolites of plants. Therefore, the ideal characteristics of SHAM should be almost nontoxic to phytopathogens and have no significant effect on control efficacy of fungicides. However, this study showed that the average effective concentration for 50% inhibition (EC50) of mycelial growth values of SHAM were 97.5 and 401.4 µg/ml for Sclerotinia sclerotiorum and Botrytis cinerea, respectively. EC50 values of the three QoI fungicides azoxystrobin, kresoxim-methyl, and trifloxystrobin in the presence of SHAM at 20 and 80 µg/ml for S. sclerotiorum and B. cinerea, respectively, declined by 52.7 to 78.1% compared with those without SHAM. For the dicarboximide fungicide dimethachlone, the average EC50 values in the presence of SHAM declined by 18.2% (P = 0.008) for S. sclerotiorum and 35.9% (P = 0.012) for B. cinerea. Pot experiments showed that SHAM increased control efficacy of the three QoI fungicides against the two pathogens by 43 to 83%. For dimethachlone, SHAM increased control efficacy by 134% for S. sclerotiorum and 86% for B. cinerea. Biochemical studies showed that SHAM significantly inhibited peroxidase activity (P = 0.024) of B. cinerea and esterase activity (P = 0.015) of S. sclerotiorum. The strong inhibitions of SHAM per se on mycelial growth of B. cinerea and S. sclerotiorum and significant influences on the sensitivity of the two pathogens to both the QoI fungicides and dimethachlone as well as inhibitions on peroxidase and esterase indicate that SHAM should not be added in the in vitro assay of sensitivity to the QoI fungicides.


Assuntos
Ascomicetos , Botrytis , Farmacorresistência Fúngica , Fungicidas Industriais , Salicilamidas , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Salicilamidas/farmacologia
2.
Eur J Med Chem ; 173: 90-98, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986574

RESUMO

As a group of biologically active compounds, polyether antibiotics (ionophores) show a broad spectrum of interesting pharmacological properties, ranging from anti-bacterial to anti-cancer activities. There is increasing evidence that ionophores, including salinomycin (SAL), and their semi-synthetic analogues are promising candidates for the development of drugs against parasitic diseases. Our previous studies have shown that esterification and amidation of the C1 carboxylate moiety of SAL provides compounds with potent activity against Trypanosoma brucei, protozoan parasites responsible for African trypanosomiasis. In this paper, we present the synthetic pathways, crystal structures and anti-trypanosomal activity of C1 esters, amides and hydroxamic acid conjugates of SAL, its C20-oxo and propargylamine analogues as well novel C1/C20 doubly modified derivatives. Evaluation of the trypanocidal and cytotoxic activity using bloodstream forms of T. brucei and human myeloid HL-60 cells revealed that the single-modified C20-oxo and propargylamine precursor molecules 10 and 16 were the most anti-trypanosomal and selective compounds with 50% growth inhibition (GI50) values of 0.037 and 0.035 µM, and selectivity indices of 252 and 300, respectively. Also the salicylhydroxamic acid conjugate of SAL (compound 9) as well as benzhydroxamic acid and salicylhydroxamic acid conjugates of 10 (compounds 11 and 12) showed promising trypanocidal activities with GI50 values between 0.032 and 0.035 µM but less favorable selectivities. The findings confirm that modification of SAL can result in derivatives with improved trypanocidal activity that might be interesting lead compounds for further anti-trypanosomal drug development.


Assuntos
Ácidos Hidroxâmicos/farmacologia , Salicilamidas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Salicilamidas/síntese química , Salicilamidas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Células Tumorais Cultivadas
3.
Eur J Pharm Sci ; 133: 59-68, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30910648

RESUMO

Cocrystal formation may affect manufacturability (flow, compaction and processability) as well as solubility/dissolution, hygroscopicity and stability properties of drugs. Therefore, cocrystallization could be used to improve the pharmaceutical properties of low-soluble drugs such as ethenzamide. In this project, solid-state nuclear magnetic resonance and Fourier transform infrared spectroscopy studies were performed for ethenzamide-glutaric acid to obtain more information about the ethenzamide cocrystallization process. The impact of the grinding time of the physical mixture (ethenzamide-glutaric acid) on cocrystal formation and the further spontaneous cocrystallization was evaluated using spectroscopic methods and curve-fitting analysis of the spectra. The influence of pressure on the yield of cocrystal formation was also described. Additionally, studies on the effect of magic-angle spinning during solid-state nuclear magnetic resonance spectra collection on the initiation of cocrystal formation, have been performed. Based on this research, conclusions regarding the influence of the different external factors, such as pressure during the tableting process and grinding time, on the cocrystal formation have been drawn for ethenzamide cocrystals.


Assuntos
Glutaratos/química , Salicilamidas/química , Cristalização , Composição de Medicamentos , Espectroscopia de Ressonância Magnética , Pressão , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos
4.
Spectrochim Acta A Mol Biomol Spectrosc ; 214: 476-486, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30807945

RESUMO

A systematic study on sulfonamide derivatives with salicylamide core is presented for possible use in pharmaceutical applications. The molecular structure of eight different compounds has been investigated by FTIR in the frequency range 4000-400 cm-1 to recognize the possible geometrical shape of the molecules needed to uniquely identify the activity of molecule in cancer cell. The electronic charge distribution of these different compounds is further illustrated by UV-Vis spectroscopy in the frequency range 190-1100 nm. The theoretical results obtained from molecular modeling calculations showed that the hydrogen bonds between the OH, CO, NH, and/or CH groups vary from one compound to the other regarding their number and bond length. This confirms the experimental FTIR results regarding the position and broadening of the OH and NH groups due to free rotation of the amide group because of changing the compounds structure by adding different groups to the last phenyl ring. The hydrogen bonds take different directions and values from one compound to the other, which seems to be the most important factor regarding the activity of these different compounds in cancer cell. Both theoretical molecular modeling calculations and FTIR experimental results have strongly evaluated the relation between the chemical structure of 5-chloro-N (4-sulfamoylbenzyl) salicylamide derivatives and their biological activities.


Assuntos
Modelos Moleculares , Salicilamidas/química , Ligações de Hidrogênio , Estrutura Molecular , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier
5.
MBio ; 10(1)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696734

RESUMO

The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we made use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans We found that use of the nitric oxide donor sodium nitroprusside (SNP) and of the alternative oxidase inhibitor salicylhydroxamic acid (SHAM) prevents respiration and leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo We propose that treatment with SNP plus SHAM (SNP+SHAM) leads to transcriptional changes that drive cell wall rearrangement but which also prime cells to activate the transition to hyphal growth. In line with this, we found that pretreatment of C. albicans with SNP+SHAM led to an increase in virulence. Our data reveal strong links between respiration, cell wall remodeling, and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals that are not damaging to the mammalian host but that we need to develop a deeper understanding of the roles of mitochondria in cellular signaling if they are to be developed successfully as a target for new antifungals.IMPORTANCE Current approaches to tackling fungal infections are limited, and new targets must be identified to protect against the emergence of resistant strains. We investigated the potential of targeting mitochondria, which are organelles required for energy production, growth, and virulence, in the human fungal pathogen Candida albicans Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However, release of C. albicans cells from respiratory inhibition appears to activate a stress response that increases the levels of traits associated with virulence. Our results make it clear that mitochondria represent a valid target for the development of antifungal strategies but that we must determine the mechanisms by which they regulate stress signaling and virulence ahead of successful therapeutic advance.


Assuntos
Candida albicans/imunologia , Parede Celular/imunologia , Transporte de Elétrons/efeitos dos fármacos , Macrófagos/imunologia , Oxigênio/metabolismo , Animais , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Candidíase/microbiologia , Candidíase/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Rim/patologia , Camundongos , Nitroprussiato/metabolismo , Salicilamidas/metabolismo , Virulência/efeitos dos fármacos , Peixe-Zebra
6.
Int J Pharm ; 559: 210-219, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30682448

RESUMO

This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing experiments on the scale of 5 and up to 100 kg/lot, using the same raw materials. Three technologies were tested and compared: (i) batch technology using fluidized bed granulation, (ii) batch technology using high shear granulation, (iii) continuous technology using high shear granulation. In the full-scale experiment, in all three technologies including continuous technology, the quality of the tablets fulfilled the target values regarding hardness, active pharmaceutical ingredient content, and dissolution. The granules produced by different technologies, however, presented varying attributes regarding granule size distribution, loose bulk density, or scanning electron microscope images. The process performance, more specifically the yield, was slightly better for batch technologies than for the continuous technology, mainly due to losses in the start-up operation. Notably, this study has shown that continuous technology, which is generally believed to not entail scale-up procedures, could in fact, require parameter adjustment for prolonged operation. The results provided suggestions for improvements to implement large-scale continuous technologies in the pharmaceutical industry.


Assuntos
Salicilamidas/química , Comprimidos/química , Química Farmacêutica/métodos , Excipientes/química , Dureza/efeitos dos fármacos , Tamanho da Partícula , Solubilidade/efeitos dos fármacos , Tecnologia Farmacêutica/métodos
7.
Molecules ; 23(12)2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30545145

RESUMO

A primary amine-salicylamide derived from chiral trans-cyclohexane-1,2-diamine was used as an organocatalyst for the enantioselective conjugate addition of aldehydes, mainly α,α-disubstituted to N-substituted maleimides. The reaction was performed in toluene as a solvent at room temperature. The corresponding enantioenriched adducts were obtained with high yields and enantioselectivities up to 94%. Theoretical calculations were used to justify the stereoinduction.


Assuntos
Aldeídos/química , Maleimidas/química , Salicilamidas/química , Técnicas de Química Sintética , Cicloexilaminas/química , Diaminas , Estereoisomerismo
8.
J Am Chem Soc ; 140(5): 1774-1782, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29300464

RESUMO

Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.


Assuntos
Antibacterianos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pirrolidinas/farmacologia , Salicilamidas/farmacologia , Succinato Desidrogenase/antagonistas & inibidores , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/metabolismo , Pirrolidinas/química , Salicilamidas/química , Succinato Desidrogenase/metabolismo
9.
Sci Rep ; 8(1): 897, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343833

RESUMO

The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments. We overcame the limitations of static docking by using large-scale high-throughput molecular dynamics (MD) simulations and Markov state models (MSMs) to determine an alternative pose consistent with the mutation data. The new pose maintains critical interactions observed in the D3R/eticlopride X-ray crystal structure and suggests that a cryptic pocket forms due to the shift of a highly conserved residue, F6.52. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery.


Assuntos
Receptores de Dopamina D3/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Sítios de Ligação/fisiologia , Linhagem Celular , Cristalografia por Raios X/métodos , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida/métodos , Ligação Proteica/fisiologia , Salicilamidas/química , Salicilamidas/metabolismo , Células Sf9
10.
Curr Drug Deliv ; 15(2): 219-226, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-27758690

RESUMO

BACKGROUND: Fluoroquinolones, the synthetic antibacterial agents are being successfully utilized against bacterial infections, since the time immemorial. Despite of enormous useful features, these drugs are associated with some limitations also. Large number of efforts has been made by various scientists to improve pharmacokinetic properties of these drugs and hence, to overcome the limitations associated with them. OBJECTIVES: The aim of this paper is to introduce a novel scheme for synthesis of prodrug with improved pharmacokinetic properties i.e., lipophilicity and consequently, modified bioavailability of norfloxacin. METHODS: Fatty acid hydrazide of selected fatty acid was synthesized followed by preparation of 5-formyl salicylamide. N-Mannich base of norfloxacin was synthesized by reacting norfloxacin with 5-formyl salicylamide. The prodrug was obtained by covalently coupling this N-Mannich base of norfloxacin with fatty acid hydrazide. The synthesized lipid based prodrug was evaluated for partition coefficient by shake flask method and screened for antimicrobial activity against selected strains. Drug content determination and in vitro dissolution studies utilizing HPLC were also carried out. RESULTS: The synthesized prodrug was found to exhibit improved partition coefficient (1.15) when compared with parent drug, norfloxacin (0.46). The results of antimicrobial evaluation indicate promising antibacterial and antifungal activity. CONCLUSION: The synthesized prodrug proved to be a good antimicrobial substance due to improved lipophilicity and would be expected to be used as a suitable candidate for exploration of possible utilities in treatment of bacterial infections in forthcoming time.


Assuntos
Antibacterianos/química , Lipídeos/química , Norfloxacino/química , Pró-Fármacos/química , Antibacterianos/farmacocinética , Antifúngicos/química , Antifúngicos/farmacocinética , Disponibilidade Biológica , Fluoroquinolonas/química , Norfloxacino/farmacocinética , Pró-Fármacos/farmacocinética , Salicilamidas/química , Solubilidade/efeitos dos fármacos
11.
Neuropsychopharmacology ; 43(2): 313-324, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28741626

RESUMO

Maladaptive decision making is associated with several neuropsychiatric disorders, including problem gambling and suicidal behavior. The prevalence of these disorders is higher in men vs women, suggesting gender-dependent regulation of their pathophysiology underpinnings. We assessed sex differences in decision making using the rat version of the Iowa gambling task. Female rats identified the most optimal choice from session 1, whereas male rats from session 5. Male, but not female rats, progressively improved their advantageous option responding and surpassed females. Estrus cycle phase did not affect decision making. To test whether pharmacological manipulations targeting the dopaminergic and stress systems affect decision making in a sex-dependent manner, male and female rats received injections of a dopamine D2 receptor (D2R) antagonist (eticlopride), D2R agonist (quinpirole), corticotropin-releasing factor 1 (CRF1) antagonist (antalarmin), and α2-adrenergic receptor antagonist (yohimbine; used as a pharmacological stressor). Alterations in mRNA levels of D2R and CRF1 were also assessed. Eticlopride decreased advantageous responding in male, but not female rats, whereas quinpirole decreased advantageous responding specifically in females. Yohimbine dose-dependently decreased advantageous responding in female rats, whereas decreased advantageous responding was only observed at higher doses in males. Antalarmin increased optimal choice responding only in female rats. Higher Drd2 and Crhr1 expression in the amygdala were observed in female vs male rats. Higher amygdalar Crhr1 expression was negatively correlated with advantageous responding specifically in females. This study demonstrates the relevance of dopaminergic- and stress-dependent sex differences to maladaptive decision making.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Tonsila do Cerebelo/metabolismo , Comportamento Animal/fisiologia , Tomada de Decisões/fisiologia , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Dopamina D2/metabolismo , Caracteres Sexuais , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Feminino , Masculino , Pirimidinas/farmacologia , Pirróis/farmacologia , Quimpirol/farmacologia , Ratos , Ratos Long-Evans , Receptores de Dopamina D2/agonistas , Salicilamidas/farmacologia , Ioimbina/farmacologia
12.
Int J Pharm ; 532(1): 82-89, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-28859939

RESUMO

In this study, we evaluated the correlation between the response surfaces for the tablet characteristics of placebo and active pharmaceutical ingredient (API)-containing tablets. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Ten tablet formulations were prepared. The tensile strength (TS) and disintegration time (DT) of tablets were measured as tablet characteristics. The response surfaces for TS and DT were estimated using a nonlinear response surface method incorporating multivariate spline interpolation, and were then compared with those of placebo tablets. A correlation was clearly observed for TS and DT of all APIs, although the value of the response surfaces for TS and DT was highly dependent on the type of API used. Based on this knowledge, the response surfaces for TS and DT of API-containing tablets were predicted from only two and four formulations using regression expression and placebo tablet data, respectively. The results from the evaluation of prediction accuracy showed that this method accurately predicted TS and DT, suggesting that it could construct a reliable response surface for TS and DT with a small number of samples. This technique assists in the effective estimation of the relationships between design variables and pharmaceutical responses during pharmaceutical development.


Assuntos
Desenho de Drogas , Comprimidos/química , Acetaminofen/química , Celulose/química , Composição de Medicamentos , Excipientes/química , Lactose/química , Niacina/química , Placebos/química , Pressão , Piridoxina/química , Salicilamidas/química , Amido/química , Ácidos Esteáricos/química
13.
Behav Neurosci ; 131(5): 392-405, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28956947

RESUMO

Nucleus accumbens core (NAcc) has been implicated in impulsive choice, as measured in delay discounting. The role of dopamine (DA) in impulsive choice has received considerable attention, whereas glutamate (Glu) has recently been shown to be an important mediator of discounting. However, research has not examined how DA or Glu receptors in NAcc mediate different aspects of delay discounting performance, that is, (a) sensitivity to reinforcer magnitude and (b) sensitivity to delayed reinforcement. Adult male Sprague-Dawley rats were first trained in a delay discounting task, in which the delay to a large magnitude food reinforcer increased across blocks of trials. Following behavioral training, rats received bilateral implantation of guide cannulas into NAcc. Half of the rats (n = 12) received infusions of the DA-selective ligands SKF 38393 (D1-like agonist: 0.03 or 0.1 µg), SCH 23390 (D1-like antagonist: 0.3 or 1.0 µg), quinpirole (D2-like agonist: 0.3 or 1.0 µg), and eticlopride (D2-like antagonist: 0.3 or 1.0 µg). The other half received infusions of the ionotropic Glu ligands MK-801 (NMDA uncompetitive antagonist: 0.3 or 1.0 µg), AP-5 (NMDA competitive antagonist: 0.3 or 1.0 µg), ifenprodil (noncompetitive antagonist at NR2B-containing NMDA receptors: 0.3 or 1.0 µg), and CNQX (AMPA competitive antagonist: 0.2 or 0.5 µg). Results showed that SCH 23390 (0.3 µg) decreased sensitivity to reinforcer magnitude without altering impulsive choice, whereas ifenprodil (1.0 µg) decreased sensitivity to delayed reinforcement (i.e., impulsive choice). The current results show that DA and NMDA receptors in NAcc mediate distinct aspects of discounting performance. (PsycINFO Database Record


Assuntos
Desvalorização pelo Atraso/efeitos dos fármacos , Dopamina/farmacologia , Ácido Glutâmico/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina , Animais , Benzazepinas , Comportamento de Escolha/efeitos dos fármacos , Dopamina/administração & dosagem , Ácido Glutâmico/metabolismo , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Quimpirol , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Reforço (Psicologia) , Salicilamidas
14.
Eur J Pharm Sci ; 107: 87-96, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28687528

RESUMO

New theoretical screening procedure was proposed for appropriate selection of potential cocrystal formers possessing the ability of enhancing dissolution rates of drugs. The procedure relies on the training set comprising 102 positive and 17 negative cases of cocrystals found in the literature. Despite the fact that the only available data were of qualitative character, performed statistical analysis using binary classification allowed to formulate quantitative criterions. Among considered 3679 molecular descriptors the relative value of lipoaffinity index, expressed as the difference between values calculated for active compound and excipient, has been found as the most appropriate measure suited for discrimination of positive and negative cases. Assuming 5% precision, the applied classification criterion led to inclusion of 70% positive cases in the final prediction. Since lipoaffinity index is a molecular descriptor computed using only 2D information about a chemical structure, its estimation is straightforward and computationally inexpensive. The inclusion of an additional criterion quantifying the cocrystallization probability leads to the following conjunction criterions Hmix<-0.18 and ΔLA>3.61, allowing for identification of dissolution rate enhancers. The screening procedure was applied for finding the most promising coformers of such drugs as Iloperidone, Ritonavir, Carbamazepine and Enthenzamide.


Assuntos
Preparações Farmacêuticas/química , Carbamazepina/química , Cristalização , Liberação Controlada de Fármacos , Excipientes/química , Ritonavir/química , Salicilamidas/química
15.
Neurosci Bull ; 33(4): 413-422, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28585114

RESUMO

The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamus in decisional impulsivity. In the present study, rats were tested using a delay discounting task and divided into three groups: high impulsivity (HI), medium impulsivity (MI), and low impulsivity (LI). Subsequent in vivo voxel-based magnetic resonance imaging revealed that the HI rats displayed a markedly reduced density of gray matter in the lateral thalamus compared with the LI rats. In the MI rats, the dopamine D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride was microinjected into the lateral thalamus. SCH23390 significantly decreased their choice of a large, delayed reward and increased their omission of lever presses. In contrast, eticlopride increased the choice of a large, delayed reward but had no effect on the omissions. Together, our results indicate that the lateral thalamus is involved in decisional impulsivity, and dopamine D1 and D2 receptors in the lateral thalamus have distinct effects on decisional impulsive behaviors in rats. These results provide a new insight into the dopamine signaling in the lateral thalamus in decisional impulsivity.


Assuntos
Tomada de Decisões/fisiologia , Comportamento Impulsivo/fisiologia , Receptores de Dopamina D1/metabolismo , Tálamo/metabolismo , Animais , Benzazepinas/farmacologia , Tomada de Decisões/efeitos dos fármacos , Desvalorização pelo Atraso/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Substância Cinzenta/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Comportamento Impulsivo/efeitos dos fármacos , Imagem por Ressonância Magnética , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley , Salicilamidas/farmacologia , Tálamo/efeitos dos fármacos , Fatores de Tempo
16.
Neuropharmacology ; 123: 249-260, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28487067

RESUMO

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Pirimidinas/farmacologia , Salicilamidas/farmacologia , Estirenos/farmacologia , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , AMP Cíclico/metabolismo , Desvalorização pelo Atraso/efeitos dos fármacos , Desvalorização pelo Atraso/fisiologia , Antagonistas dos Receptores de Dopamina D2/sangue , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/sangue , Agonistas de Aminoácidos Excitatórios/líquido cefalorraquidiano , Comportamento Impulsivo/fisiologia , Masculino , Atividade Motora/fisiologia , Psicotrópicos/farmacologia , Pirimidinas/sangue , Pirimidinas/líquido cefalorraquidiano , Ratos , Receptores de Dopamina D2/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Salicilamidas/sangue , Estirenos/sangue , Estirenos/líquido cefalorraquidiano , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia
17.
Eur Neuropsychopharmacol ; 27(5): 462-469, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28377075

RESUMO

Alterations in the dopamine system are hypothesized to influence the expression of social anxiety disorder (SAD) symptoms. However, molecular imaging studies comparing dopamine function between patients and control subjects have yielded conflicting results. Importantly, while all previous investigations focused on the striatum, findings from activation and blood flow studies indicate that prefrontal and limbic brain regions have a central role in the pathophysiology. The objective of this study was to investigate extrastriatal dopamine D2-receptor (D2-R) availability in SAD. We examined 12 SAD patients and 16 healthy controls using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB457. Parametric images of D2-R binding potential were derived using the Logan graphical method with cerebellum as reference region. Two-tailed one-way independent ANCOVAs, with age as covariate, were used to examine differences in D2-R availability between groups using both region-based and voxel-wise analyses. The region-based analysis showed a medium effect size of higher D2-R levels in the orbitofrontal cortex (OFC) in patients, although this result did not remain significant after correction for multiple comparisons. The voxel-wise comparison revealed elevated D2-R availability in patients within OFC and right dorsolateral prefrontal cortex after correction for multiple comparisons. These preliminary results suggest that an aberrant extrastriatal dopamine system may be part of the disease mechanism in SAD.


Assuntos
Fobia Social/patologia , Fobia Social/reabilitação , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/metabolismo , Adulto , Análise de Variância , Mapeamento Encefálico , Isótopos de Carbono/farmacocinética , Antagonistas de Dopamina/farmacocinética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fobia Social/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Pirrolidinas/farmacocinética , Salicilamidas/farmacocinética , Adulto Jovem
18.
Int J Pharm ; 531(2): 543-549, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28450165

RESUMO

Various ternary Guest 2/(Guest 1/γ-cyclodextrin (CD)) complexes were prepared using a cogrinding and subsequent heating method, wherein Guest 1 was incorporated in the cavity of γ-CD and Guest 2 was incorporated into the intermolecular spaces between γ-CD columns. Dissolution fluxes of Guest 1 and Guest 2 from all ternary complexes were almost identical. The dissolution flux of flurbiprofen (Guest 1) from the ternary complexes depended on the solubility of Guest 2 drugs (naproxen

Assuntos
Portadores de Fármacos/química , gama-Ciclodextrinas/química , Química Farmacêutica , Flurbiprofeno/química , Cetoprofeno/química , Naproxeno/química , Salicilamidas/química , Solubilidade
19.
Eur J Med Chem ; 135: 142-158, 2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28441582

RESUMO

Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI50 values. The most potent compounds (series 4 and 6) were further assayed for their inhibition of chymotrypsin-like protease activity of the 26S proteasome in U266 cells. The majority of compounds inhibited the proteasome in mid-nanomolar concentrations (IC50 ranging from 57 to 197 nM) and it correlated with cellular potency. In a cell based assay involving green fluorescence protein (GFP) fused to a short degron that is rapidly degraded by a proteasome the compounds induced accumulation of GFP, visualised and quantified by live-cell imaging. Levels of polyubiquitinated proteins in U266 cells treated by compound 4m were also analyzed by immunoblotting, revealing a typical high molecular mass smear of ubiquitin conjugates. Finally, apoptotic cell death in treated U266 cells was detected biochemically by measuring the activity of caspases 3 and 7 in lysates and by immunoblotting of caspase 7, its substrate poly(ADP-ribose)polymerase, and Mcl-1, which all together showed changes typical for apoptosis. All these observations were in agreement with expected cellular mechanism of action and confirmed proteasome targeting by prepared O-benzyl salicylamides.


Assuntos
Antineoplásicos/farmacologia , Leucina/farmacologia , Fenilalanina/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Salicilamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucina/química , Estrutura Molecular , Fenilalanina/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Salicilamidas/síntese química , Salicilamidas/química , Relação Estrutura-Atividade
20.
Int J Pharm ; 522(1-2): 80-89, 2017 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-28274662

RESUMO

The aim of this study was to evaluate the stability and solubility of the polymorphic forms of the ethenzamide (ET) - gentisic acid (GA) cocrystals during standard technological processes leading to tablet formation, such as compression and excipient addition. In this work two polymorphic forms of pharmaceutical cocrystals (ETGA) were characterized by 13C and 15N solid-state nuclear magnetic resonance and Fourier transformed infrared spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of chemical shielding constants.Polymorphs of cocrystals were easily identified and characterized on the basis of solid-state spectroscopic studies. ETGA cocrystals behaviour during direct compressionand tabletting with excipient addition were tested. In order to choose the best tablet composition with suitable properties for the pharmaceutical industry dissolution profile studies of tablets containing polymorphic forms of cocrystals with selected excipients were carried out.


Assuntos
Gentisatos/química , Salicilamidas/química , Química Farmacêutica , Cristalização , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos
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