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1.
Mikrochim Acta ; 188(6): 186, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33978843

RESUMO

Metal-organic framework (UiO-66-NH2)-incorporated organic polymer monolith was prepared by thermal polymerization. By virtue of the superior physical and chemical properties, the UiO-66-NH2-modified organic monolith was then functionalized by chiral selector cellulase via the condensation reaction between the primary amino groups and aldehyde groups. The synthesized materials were characterized by Fourier transform infrared spectroscopy, high-resolution transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectrometry, thermogravimetric analysis, and nitrogen sorption isotherm. The cellulase@poly(glycidyl methacrylate-UiO-66-NH2-ethylene glycol dimethacrylate) (cellulase@poly(GMA-UiO-66-NH2-EDMA)) monolith was applied to enantiomerically separate the basic racemic forms of metoprolol, atenolol, esmolol, bisoprolol, and propranolol. In contrast to the cellulase@poly(GMA-co-EDMA) monolith without UiO-66-NH2, the cellulase@poly(GMA-UiO-66-NH2-EDMA) monolith reveals significantly improved enantiodiscrimination performance for metoprolol (Rs: 0 → 1.67), atenolol (Rs: 0 → 1.50), esmolol (Rs: 0 → 1.52), bisoprolol (Rs: 0 → 0.36), and propranolol (Rs: 0 → 0.44). The immobilization pH of cellulase, buffer pH, UiO-66-NH2 concentration, and the proportion of organic modifier were evaluated in detail with enantiomerically separating chiral molecules. The intra-day, inter-day, column-to-column, and inter-batch precision have been discussed, the result was preferable, and the relative standard deviation (RSD) of separation parameters was <4.3%. Schematic representation of the preparation of a UiO-66-NH2-modified organic polymer monolith for enantioseparating five racemic ß-blockers. UiO-66-NH2 was synthesized and converted into a monolith as the stationary phase. Then, the modified monolith containing cellulase as the chiral selector was applied in a capillary electrochromatography system for enantioseparating chiral drugs.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/isolamento & purificação , Celulase/química , Enzimas Imobilizadas/química , Estruturas Metalorgânicas/química , Fenoxipropanolaminas/isolamento & purificação , Antagonistas de Receptores Adrenérgicos beta 1/química , Eletrocromatografia Capilar , Hypocreales/enzimologia , Metacrilatos/química , Fenoxipropanolaminas/química , Ácidos Polimetacrílicos/química , Estereoisomerismo , Zircônio/química
2.
Artigo em Inglês | MEDLINE | ID: mdl-31704621

RESUMO

A novel dispersive liquid-liquid microextraction (DLLME) method using ionic liquids (ILs) followed by high-performance liquid chromatography-diode array detector (HPLC-DAD) has been devised to specify Atenolol, Atenolol, Metoprolol and Propranolol in blood real samples. Fourteen effective parameters in DLLME process, including pH of aqueous sample, volume of the dispersion and extraction solvents and ionic strength of donor phase, etc.; were screened using fractional factorial screening methodology (FFSM) based on Placket-Burman design (PBD) and subsequently were optimized by response surface methodology using central composite design (CCD). A mixture of IL (1-butyl-3-methyl imidazolium hexa fluoro phosphate) and disperser solvent (methanol) was quickly injected into the sample solution leading to the formation of the semi cloudy solution. Afterwards, HPLC-DAD was applied to examine the sedimented IL drop. The detection limits (LOD) for all analytes ranges were 0.00268-0.00300 µg L-1. The relative standard deviations (RSDs) for seven experiments were between 3.832% and 4.432% for three target analytes. The proposed method illustrated wide dynamic linear range (DLR, 0.009-1 µg L-1), desirable linearity (R2 ≈ 0.997), high enrichment factors (EF, 313-330) and good relative recoveries (RR, 96-104%). Clear separation and desirable chromatogram was quickly reached without the intervention of the matrix. Besides, a comparison of this method with previous methods indicated that the suggested method is a reproducible, quick and dependable sample pretreatment technique for extraction and determination of pharmaceuticals in blood sample.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Microextração em Fase Líquida/métodos , Fenoxipropanolaminas/sangue , Adulto , Humanos , Líquidos Iônicos , Limite de Detecção , Modelos Lineares , Masculino , Fenoxipropanolaminas/química , Fenoxipropanolaminas/isolamento & purificação , Reprodutibilidade dos Testes , Adulto Jovem
3.
Pharmacol Biochem Behav ; 170: 14-24, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29729290

RESUMO

Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i.p.). Contrary, all compounds 2-8 showed moderate protection in the strychnine (STR)-induced convulsion model following acute pretreatment (10 mg/kg, i.p.). Moreover, the acute systemic administration of H3R antagonist 6 (10 mg/kg, i.p.) significantly prolonged latency time for MES convulsions. Furthermore, the anticonvulsant effect observed with compound 6 in MES-model was entirely abrogated when rats were co-injected with the brain penetrant H1R antagonist pyrilamine (PYR) but not the brain penetrant H2R antagonist zolantidine (ZOL). However, PYR and ZOL failed to abolish the full protection provided by the H3R antagonist 6 in PTZ- and STR-models. No mutagenic or antiproliferative effects or potential metabolic interactions were shown for compound 6 when assessing its antiproliferative activities and metabolic profiling applying in-vitro methods. These findings demonstrate the potential of non-imidazole H3R antagonists as novel antiepileptic drugs (AEDs) either for single use or in addition to currently available epilepsy medications.


Assuntos
Anticonvulsivantes/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Convulsões/tratamento farmacológico , Animais , Benzotiazóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Pirilamina/farmacologia , Ratos , Ratos Wistar , Tempo de Reação , Estricnina/farmacologia
4.
Biomed Chromatogr ; 32(6): e4196, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29357403

RESUMO

A rapid, robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for bioanalysis of TJ0711, a novel vasodilatory ß-blocker in dog plasma. This assay is able to chromatographically separate TJ0711 from its isobaric metabolite as well as glucuronide conjugates. Chromatographic separation was achieved on a Welch Ultimate-XB C18 column (2.1 × 100 mm, 3 µm). The analyte and internal standard (propranolol) were extracted from plasma by liquid-liquid extraction using ethyl acetate. The mass spectrometric detection was carried out in positive ion multiple reaction monitoring mode. Good linearity was obtained over the concentration range of 0.5-500 ng/mL (r > 0.99) for TJ0711. Moreover, the method had good accuracy (RE ranging from -2.70 to -0.32%) and precision (RSD < 7.55%). TJ0711 was stable in dog plasma for at least 6 h at ambient temperature, for at least 30 days at -20°C and after three freeze-thaw cycles. This method was successfully applied to a preclinical pharmacokinetic study and the results demonstrated linear pharmacokinetics of TJ0711 over a dose range from 0.03 to 0.3 mg/kg. No significant gender differences were observed in TJ0711 plasma pharmacokinetic parameters.


Assuntos
Cromatografia Líquida/métodos , Fenoxipropanolaminas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Cães , Estabilidade de Medicamentos , Feminino , Modelos Lineares , Masculino , Fenoxipropanolaminas/química , Fenoxipropanolaminas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
5.
Bioorg Med Chem Lett ; 27(23): 5172-5178, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29113763

RESUMO

New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the ß5 and ß1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design.


Assuntos
Fenoxipropanolaminas/química , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/química , Animais , Sítios de Ligação , Domínio Catalítico , Bovinos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Fenoxipropanolaminas/síntese química , Fenoxipropanolaminas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/metabolismo , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Relação Estrutura-Atividade
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 46(1): 1-6, 2017 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-28436624

RESUMO

Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed. Results: Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all P<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all P<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all P<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine. Conclusion: Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.


Assuntos
Transtornos da Memória/tratamento farmacológico , Receptores Histamínicos H2/efeitos dos fármacos , Receptores Histamínicos H2/fisiologia , Memória Espacial/efeitos dos fármacos , Animais , Benzotiazóis/farmacologia , Química Encefálica/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/complicações , Hipocampo/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Histidina/farmacologia , Hipotálamo/química , Excitação Neurológica/fisiologia , Transtornos da Memória/etiologia , Pentilenotetrazol , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Pirilamina/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Fluorescência , Tálamo/química
7.
Int J Neuropsychopharmacol ; 20(5): 392-399, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339575

RESUMO

Background: The integrity of the brain histaminergic system is necessary for the unfolding of homeostatic and cognitive processes through the recruitment of alternative circuits with distinct temporal patterns. We recently demonstrated that the fat-sensing lipid mediator oleoylethanolamide indirectly activates histaminergic neurons to exerts its hypophagic effects. The present experiments investigated whether histaminergic neurotransmission is necessary also for the modulation of emotional memory induced by oleoylethanolamide in a contextual fear conditioning paradigm. Methods: We examined the acute effect of i.p. administration of oleoylethanolamide immediately posttraining in the contextual fear conditioning test. Retention test was performed 72 hours after training. To test the participation of the brain histaminergic system in the cognitive effect of oleoylethanolamide, we depleted rats of brain histamine with an i.c.v. injection of alpha-fluoromethylhistidine (a suicide inhibitor of histidine decarboxylase) or bilateral intra-amygdala infusions of histamine H1 or H2 receptor antagonists. We also examined the effect of oleoylethanolamide on histamine release in the amygdala using in vivo microdialysis. Results: Posttraining administration of oleoylethanolamide enhanced freezing time at retention. This effect was blocked by both i.c.v. infusions of alpha-fluoromethylhistidine or by intra-amygdala infusions of either pyrilamine or zolantidine (H1 and H2 receptor antagonists, respectively). Microdialysis experiments showed that oleoylethanolamide increased histamine release from the amygdala of freely moving rats. Conclusions: Our results suggest that activation of the histaminergic system in the amygdala has a "permissive" role on the memory-enhancing effects of oleoylethanolamide. Hence, targeting the H1 and H2 receptors may modify the expression of emotional memory and reduce dysfunctional aversive memories as found in phobias and posttraumatic stress disorder.


Assuntos
Cognição/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Endocanabinoides/farmacologia , Medo/efeitos dos fármacos , Histamina/metabolismo , Ácidos Oleicos/farmacologia , Análise de Variância , Animais , Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Histamínicos/farmacologia , Hipotálamo/efeitos dos fármacos , Masculino , Metilistidinas/farmacologia , Microdiálise , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Wistar
8.
Eur J Drug Metab Pharmacokinet ; 42(3): 471-487, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27447171

RESUMO

BACKGROUND AND OBJECTIVES: The US Food and Drug Administration, World Health Organization and European Medicines Agency have allowed biowaiver for some BCS class III drugs, but shortened the requisite dissolution time of BCS class III drugs from 30 to 15 min, considering their site-specific absorption and others risk. The objective of this study was to assess the effects of site-specific absorption, low absorbed fraction (F a) and gastric emptying rate on the biowaiver extension of BCS class III drugs. METHODS: The oral absorption of BCS class III drugs nadolol, acebutolol and atenolol which were P-gp substrates, was simulated using GastroPlus software with physiological parameters reflecting site-specific and site-independent absorption. Then, the simulation results were compared with the experimental data in literature. Simulation with different dissolution rates (>85 % solubility, T 85 % = 15-180 min) was performed to predict absorption (maximum concentration, C max and area under the concentration-time curve from time 0 to infinity, AUC0-inf) of the above model/virtual drugs (F a 3.81-80.14 %). RESULTS: The results of this study indicated that the site-specific absorption and low F a magnified the effect of dissolution rate on C max and AUC0-inf. However, the oral absorption of model drugs was not sensitive to the change of gastric emptying rate from 0.1, 0.25, 0.5 to 1 h. CONCLUSIONS: Based on the results of this study, we suggest that for BCS class III drug with high F a (about >80 %), the biowaiver should extend to rapid dissolution (T 85 % = 30 min), and 30 % of F a as the boundary of intermediate permeability class (30 % < F a < 85 %).


Assuntos
Trato Gastrointestinal/metabolismo , Absorção Intestinal/fisiologia , Fenoxipropanolaminas/metabolismo , Simulação por Computador , Humanos , Modelos Biológicos , Permeabilidade , Software
9.
J Mass Spectrom ; 51(3): 207-18, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26956388

RESUMO

Identification of degradation products from trace organic compounds, which may retain the biological activity of the parent compound, is an important step in understanding the long-term effects of these compounds on the environment. Constructed wetlands have been successfully utilized to remove contaminants from wastewater effluent, including pharmacologically active compounds. However, relatively little is known about the transformation products formed during wetland treatment. In this study, three different wetland microcosm treatments were used to determine the biotransformation products of the ß-adrenoreceptor antagonists atenolol, metoprolol and propranolol. LC/ESI-Q-ToF run in the MS(E) and MS/MS modes was used to identify and characterize the degradation products through the accurate masses of precursor and product ions. The results were compared with those of a reference standard when available. Several compounds not previously described as biotransformation products produced in wetlands were identified, including propranolol-O-sulfate, 1-naphthol and the human metabolite N-deaminated metoprolol. Transformation pathways were significantly affected by microcosm conditions and differed between compounds, despite the compounds' structural similarities. Altogether, a diverse range of transformation products in wetland microcosms were identified and elucidated using high resolving MS. This work shows that transformation products are not always easily predicted, nor formed via the same pathways even for structurally similar compounds.


Assuntos
Antagonistas Adrenérgicos beta/análise , Microbiologia Ambiental , Microbiota/fisiologia , Fenoxipropanolaminas/análise , Áreas Alagadas , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/metabolismo , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Fenoxipropanolaminas/química , Fenoxipropanolaminas/metabolismo
10.
Chirality ; 28(4): 313-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26821612

RESUMO

A biocatalytic route for the synthesis of a potential ß-blocker, (S)-moprolol is reported here. Enantiopure synthesis of moprolol is mainly dependent on the chiral intermediate, 3-(2-methoxyphenoxy)-propane-1,2-diol. Various commercial lipases were screened for the enantioselective resolution of (RS)-3-(2-methoxyphenoxy)propane-1,2-diol to produce the desired enantiomer. Among them, Aspergillus niger lipase (ANL) was selected on the basis of both stereo- and regioselectivity. The optimized values of various reaction parameters were determined such as enzyme (15 mg/mL), substrate concentration (10 mM), organic solvent (toluene), reaction temperature (30 °C), and time (18 h).The optimized conditions led to achieving >49% yield with high enantiomeric excess of (S)-3-(2-methoxyphenoxy)propane-1,2-diol. The lipase-mediated catalysis showed regioselective acylation with dual stereoselectivity. Further, the enantiopure intermediate was used for the synthesis of (S)-moprolol, which afforded the desired ß-blocker.


Assuntos
Antagonistas Adrenérgicos beta/química , Lipase/química , Fenoxipropanolaminas/síntese química , Acilação , Antagonistas Adrenérgicos beta/metabolismo , Biocatálise , Catálise , Lipase/metabolismo , Propanóis/química , Estereoisomerismo
11.
Behav Brain Res ; 297: 155-64, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26467607

RESUMO

Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.


Assuntos
Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Pirróis/farmacologia , Quinazolinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Benzotiazóis/farmacologia , Modelos Animais de Doenças , Maleato de Dizocilpina , Donepezila , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Indanos/farmacologia , Masculino , Memória/fisiologia , Transtornos da Memória/metabolismo , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Pirilamina/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptores Histamínicos H3/metabolismo
12.
Neuropharmacology ; 106: 46-55, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26525191

RESUMO

It has become clear that histamine H3 receptors (H3Rs) are implicated in modulating epilepsy and memory in laboratory animals. The new non-imidazole H3R antagonist DL77 has excellent selectivity profile and shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 values of 2.1 ± 0.2 mg/kg and 8.4 ± 1.3 [nM], respectively. In the present study, the anticonvulsant effects of DL77 on maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced seizure models were investigated. Moreover, the procognitive properties of DL77 were tested on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in male Wistar rats. The results indicate that DL77 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently reduced MES-induced seizure duration, whereas no protection was observed in PTZ- or STR-induced seizures. Importantly, the protective action observed for DL77 in MES-induced seizure was comparable to that of the reference antiepileptic drug (AED) phenytoin (PHT), and was also reversed when rats were pretreated with the CNS penetrant pyrilamine (PYR) (10 mg/kg, i.p.), or with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg, i.p.). Furthermore, the procognitive studies indicate that acute pre-training systemic administration of DL77 (2.5 mg/kg, i.p.) facilitated acquisition, whereas pre-testing acute administration of DL77 (5 and 10 mg/kg, i.p.) improved retrieval. Interestingly, the procognitive effect of DL77 on retrieval was completely abrogated when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL) but not the centrally acting H1R antagonist PYR, indicating that histaminergic pathways through activation of H2Rs appear to be participating in neuronal circuits involved in retrieval processes. Taken together, our results show that DL77 demonstrates anticonvulsant properties in the MES-induced seizure model and improves cognitive performance through actions on different memory stages. Therefore, H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacological target to tackle cognitive problems associated with the chronic use of antiepileptic drugs. This article is part of the Special Issue entitled 'Histamine Receptors'.


Assuntos
Anticonvulsivantes/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nootrópicos/farmacologia , Éteres Fenílicos/farmacologia , Piperidinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Benzotiazóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Metilistaminas/farmacologia , Fenoxipropanolaminas/farmacologia , Fenitoína/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptores Histamínicos H3/metabolismo
13.
Chem Commun (Camb) ; 51(82): 15133-6, 2015 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-26324053

RESUMO

Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of ß-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.


Assuntos
Fenoxipropanolaminas/síntese química , Antiarrítmicos/síntese química , Anti-Hipertensivos/síntese química , Broncodilatadores/síntese química , Técnicas de Química Sintética , Epicloroidrina/química , Compostos de Epóxi/síntese química , Estereoisomerismo
14.
Chirality ; 27(1): 53-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25315344

RESUMO

The enantioselective pharmacokinetics of TJ0711 hydrochloride were studied in rats given different doses of rac-TJ0711 hydrochloride via intravenous and oral routes. R- and S-TJ0711 hydrochloride were both rapidly absorbed, and the average AUC0-∞ of R-TJ0711 hydrochloride was greater than that of S-TJ0711 hydrochloride after intragastric administration, with an R/S AUC ratio 1.11 and 1.35 for 30 and 50 mg/kg dose group, respectively. In contrast, the average AUC0-∞ of R-TJ0711 hydrochloride was smaller than that of S-TJ0711 hydrochloride after intravenous injection, with an R/S AUC ratio 0.57 and 0.73 for 10 and 20 mg/kg dose group, respectively. R-TJ0711 hydrochloride plasma half-lives were shorter than those of S-TJ0711 hydrochloride for all groups. AUC0-4h and Cmax between the two enantiomers were significantly different after oral administration of 50 mg/kg dose of the racemate, while no significant differences between the two enantiomers were found for all the pharmacokinetic parameters of the 30 mg/kg dose group. Significant differences between the two enantiomers were detected for nearly all the pharmacokinetic parameters after intravenous administration, except for the VZ of 20 mg/kg dose group. This study suggests that dose and route of administration will influence the enantioselectivity in the pharmacokinetics of TJ0711 hydrochloride in rats.


Assuntos
Fenoxipropanolaminas/administração & dosagem , Fenoxipropanolaminas/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Fenoxipropanolaminas/sangue , Ratos , Ratos Sprague-Dawley , Estereoisomerismo
15.
Pharmacol Res ; 90: 58-66, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25304183

RESUMO

Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10µg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.


Assuntos
Histamina/fisiologia , Hiperalgesia/fisiopatologia , Locus Cerúleo/fisiologia , Neuralgia/fisiopatologia , Neurônios Adrenérgicos/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Benzotiazóis/farmacologia , Bicuculina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Temperatura Alta , Imidazóis/farmacologia , Indanos/farmacologia , Masculino , Fenoxipropanolaminas/farmacologia , Estimulação Física , Piperidinas/farmacologia , Prazosina/farmacologia , Ratos , Receptores Adrenérgicos alfa 1/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Histamínicos/fisiologia , Nervos Espinhais/lesões
16.
Yao Xue Xue Bao ; 49(3): 419-26, 2014 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-24961117

RESUMO

To study the antiarrhythmic effect of the newly developed alpha/beta-blocker TJ0711, a variety of animal models of arrhythmia were induced by CaCl2, ouabain and ischemia/reperfusion. Glass microelectrode technique was used to observe action potentials of right ventricular papillary muscle of guinea pig. The onset time of arrhythmia induced by CaCl2 was significantly prolonged by TJ0711 at 0.75, 1.5 and 3 mg x kg(-1) doses. TJ0711 (1.5 and 3 mg x kg(-1)) can significantly shorten the ventricular tachycardia (VT) and ventricular fibrillation (VF) duration, the incidence of VF and mortality were significantly reduced. On ischemia-reperfusion-induced arrhythmic model, TJ0711 (0.25, 0.5, 1 and 2 mg x kg(-1)) can significantly reduce the ventricular premature contraction (PVC), VT, VF incidence, mortality, arrhythmia score with a dose-dependent manner. At the same time, rats serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities decreased significantly by TJ0711 (1 and 2 mg x kg(-1)). Ouabain could cause arrhythmia in guinea pigs, when TJ0711 (0.375, 0.75, 1.5 and 3 mg x kg(-1)) was given, the doses of ouabain inducing a variety of arrhythmia PVC, VT, VF, cardiac arrest (CA) were significantly increased with a dose-dependent manner. In the TJ0711 0.1-30 micromol x L(-1) concentration range, guinea pig right ventricular papillary muscle action potential RP (rest potential), APA (action potential amplitude) and V(max) (maximum velocity of depolarization) were not significantly affected. APD20, APD50 and APD90 had a shortening trend but no statistical difference with the increase of TJ0711 concentration. TJ0711 has antiarrhythmic effect on the sympathetic nerve excitement and myocardial cell high calcium animal arrhythmia model. Myocardial action potential zero phase conduction velocity and resting membrane potential were not inhibited by TJ0711. APD20, APD50 and APD90 were shortened by TJ0711 at high concentration. Its antiarrhythmic action mechanism may be besides the action of blocking beta1 receptor, may also have a strong selective blocking action on alpha1 receptor and reducing intracellular calcium concentration.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Antiarrítmicos/farmacologia , Arritmias Cardíacas , Fenoxipropanolaminas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/sangue , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Cloreto de Cálcio , Creatina Quinase/sangue , Relação Dose-Resposta a Droga , Feminino , Cobaias , Ventrículos do Coração/citologia , Lactato Desidrogenases/sangue , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ouabaína , Músculos Papilares/citologia , Fenoxipropanolaminas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
17.
Braz. j. med. biol. res ; 46(5): 440-446, maio 2013. tab, graf
Artigo em Inglês | LILACS | ID: lil-675675

RESUMO

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.


Assuntos
Animais , Masculino , Camundongos , Ansiedade/induzido quimicamente , Benzotiazóis/farmacologia , Clorfeniramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , /farmacologia , Transtornos da Memória/induzido quimicamente , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Aprendizagem em Labirinto , Microinjeções
18.
Braz J Med Biol Res ; 46(5): 440-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23598647

RESUMO

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.


Assuntos
Ansiedade/induzido quimicamente , Benzotiazóis/farmacologia , Clorfeniramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Transtornos da Memória/induzido quimicamente , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Animais , Masculino , Aprendizagem em Labirinto , Camundongos , Microinjeções
19.
Yao Xue Xue Bao ; 47(8): 1001-5, 2012 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-23162895

RESUMO

The study is to observe the effect of racemic TJ0711 on blood pressure and heart rate as well as protection of cardiovascular system of renal hypertensive rats after long-term administration. The renal hypertensive models were established by the two-kidney, one-clip (2K1C) method in Wistar rats. Four weeks later, assigned the rats whose SBP had increased at least 4 kPa randomly into 5 groups: racemic TJ0711 10, 20 and 40 mg x kg(-1) groups, carvedilol control group, model group and sham group (n=10), ig administration once daily. The changes of BP (blood press) and HR (heart rate) before and after administration were measured by tail-cuff method weekly. Plasma samples of all animals were taken in 6-8 weeks, and plasma MDA as well as renin, angiotensin II (Ang II) and endothelin-1 (ET-1) levels were measured. Left ventricle was cut off after 9 weeks, and left ventricular weight index (LVWI) and hydroxyproline were measured. The significant decrease of the BP of TJ0711 40 mg x kg(-1) group was observed after TJ0711 ig administration for 4 weeks, and this effect remained till the end of the study. In 8th week, the systolic blood pressure values were: TJ0711 40 mg x kg(-1) group 18.93 +/- 1.82 kPa (vs 21.30 +/- 2.30 kPa, P < 0.05); 20 mg x kg(-1) group 20.68 +/- 3.29 kPa (vs 22.19 +/- 2.88 kPa). The plasma MDA level of all treated groups was significantly lower than that of model group, so were the plasma renin, Ang II and ET-1 levels (P < 0.05). LVWI and hydroxyproline content of myocardial tissue decreased to some extent, but was not significant as compared with that of model group. The study showed that TJ0711 repeated dosing could reduce BP level beginning from drug administration; besides block adrenal alpha and beta receptors to play an antihypertensive role. The sustained antihypertensive effect also related to reduce plasma vasoconstrictor substances and oxidation product MDA. These effects benefited cardiovascular protection.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Renal/fisiopatologia , Fenoxipropanolaminas/farmacologia , Angiotensina II/sangue , Animais , Anti-Hipertensivos/administração & dosagem , Endotelina-1/sangue , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hidroxiprolina/metabolismo , Hipertensão Renal/sangue , Estudos Longitudinais , Masculino , Malondialdeído/sangue , Tamanho do Órgão/efeitos dos fármacos , Fenoxipropanolaminas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Renina/sangue
20.
Chem Pharm Bull (Tokyo) ; 60(5): 647-58, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22689403

RESUMO

In the search for potent and selective human ß3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human ß3-, ß2-, and ß1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the ß3-AR with functional selectivity over the ß1- and ß2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.


Assuntos
Acetamidas/química , Agonistas de Receptores Adrenérgicos beta 3/síntese química , Hipoglicemiantes/síntese química , Fenoxipropanolaminas/química , Receptores Adrenérgicos beta 3/química , Administração Oral , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Obesidade/tratamento farmacológico , Receptores Adrenérgicos beta 1/química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo
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