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1.
Bioorg Med Chem Lett ; : 127681, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189775

RESUMO

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

2.
Front Neurosci ; 14: 573633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041766

RESUMO

Background: Neuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson's disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied in vivo. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients. Methods: Seventeen neurological WD patients and 20 healthy controls were recruited for the study. Mean bulk susceptibility values and volumes of DGM were obtained from quantitative susceptibility mapping (QSM). Regions of interest including the head of the caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, red nucleus, and dentate nucleus were manually segmented. The susceptibility values and volumes of DGM in different groups were compared using a linear regression model. Correlations between susceptibility values and volumes of DGM and Unified Wilson's Disease Rating Scale (UWDRS) neurological subscores were investigated. Results: The susceptibility values of all examined DGM in WD patients were higher than those in healthy controls (P < 0.05). Volume reductions were observed in the head of the caudate nucleus, globus pallidus, putamen, thalamus, and substantia nigra of WD patients (P < 0.001). Susceptibility values were negatively correlated with the volumes of the head of the caudate nucleus (r p = -0.657, P = 0.037), putamen (r p = -0.667, P = 0.037), and thalamus (r p = -0.613, P = 0.046) in WD patients. UWDRS neurological subscores were positively correlated with the susceptibility values of all examined DGM. The susceptibility values of putamen, head of the caudate nucleus, and dentate nucleus could well predict UWDRS neurological subscores. Conclusion: Our study provided in vivo evidence that paramagnetic metal accumulation in the DGM was associated with DGM atrophy and neurological impairment. The susceptibility of DGM could be used as a biomarker to assess the severity of neurodegeneration in WD.

3.
Bioorg Med Chem Lett ; 29(24): 126769, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31699607

RESUMO

A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.


Assuntos
Antidepressivos/uso terapêutico , Piperidinas/síntese química , Piperidinas/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Antidepressivos/farmacologia , Humanos , Piperidinas/farmacologia , Inibidores de Captação de Serotonina/farmacologia
4.
Bioorg Med Chem Lett ; 29(23): 126703, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31627993

RESUMO

A series of novel aralkyl piperazine and piperidine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT1A/5-HT7 receptors affinities activity. Antidepressant activities in vivo of the selective compound were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compound 19a exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, Ki = 12 nM; 5-HT7, Ki = 3.2 nM) coupled with potent serotonin reuptake inhibition (IC50 = 14 nM) and showed a marked antidepressant-like effect in the FST and TST models.


Assuntos
Antidepressivos/uso terapêutico , Piperazina/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Antidepressivos/farmacologia , Humanos , Piperazina/farmacologia , Piperidinas/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Relação Estrutura-Atividade
5.
ACS Nano ; 13(10): 11623-11631, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31532630

RESUMO

Structural dynamics and changes in electronic structures driven by photoexcited carriers are critical issues in both semiconducting and optoelectronic nanodevices. Herein, a phase diagram for the transient states and relevant dynamic processes in multiwalled boron nitride nanotubes (BNNTs) has been extensively studied for a full reversible cycle after a fs-laser excitation in ultrafast TEMs, and the significant structural features and evolution of electronic natures have been investigated using pulsed electron diffraction and femtosecond-resolved electron energy-loss spectroscopy (EELS). It is revealed that nonthermal anisotropic alterations of the lattice apparently precede the phonon-driven thermal transients along the radial and axial directions. Ab initio calculations support these findings and show that electrons excited from the π to π* orbitals in the BN nanotubes weaken the intralayer bonds while strengthening the interlayer bonds along the radial direction. Importantly, time-resolved EELS measurements show contraction of the energy bandgap after fs-laser excitation associated with nonthermal structural transients. This fact verifies that laser-induced bandgap renormalization in semiconductors can essentially be correlated with both the rapid processes of excited carriers and nonthermal lattice evolution.

6.
J Am Chem Soc ; 141(8): 3404-3408, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30739447

RESUMO

A quaternary compound Bi3O2S2Cl, which consists of novel [BiS2Cl]2- layers, is reported. It adopts a layered structure of the space group I4/ mmm (No. 139) with lattice parameters: a = 3.927(1) Å, c = 21.720(5) Å. In this compound, bismuth and chlorine atoms form an infinite planar layer, which is unique among the bismuth halides. Superconductivity is observed in both polycrystals and single crystals, and is significantly enhanced in the samples prepared with less sulfur or at higher temperatures. By tuning the content of sulfur, Bi3O2S2Cl can be converted from a semiconductor into a superconductor. The superconducting critical temperature ranges from 2.6 to 3.5 K. Our discovery of the [BiS2Cl]2- layer opens another door in searching for the bismuth compounds with novel physical properties.

7.
Eur J Med Chem ; 144: 701-715, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29291438

RESUMO

A series of novel aralkyl piperazine derivatives were synthesized, and evaluated for their serotonin reuptake inhibitory and 5-HT1A/5-HT7 receptors affinities activity. Antidepressant activities in vivo of the compounds were screened using the forced swimming test (FST) and tail suspension test (TST). The results indicated that compounds 21k (RUI, IC50 = 31 nM; 5-HT1A, 5-HT7, ki = 62, 12 nM) and 21n (RUI, IC50 = 25 nM; 5-HT1A, 5-HT7, ki = 28, 3.3 nM) exhibited high affinities for the 5-HT1A/5-HT7 receptors coupled with potent serotonin reuptake inhibition. Specifically, the most promising compound 21n possessed a good oral pharmacokinetic properties and an acceptable hERG profile, and showed potent antidepressant-like effect in the FST and TST models.


Assuntos
Antidepressivos/farmacologia , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/síntese química , Inibidores de Captação de Serotonina/química , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 27(24): 5420-5423, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29138029

RESUMO

A series of arylalkanol and aralkyl piperazine derivatives have been synthesized and evaluated for 5-HT reuptake inhibitory abilities and binding affinities at the 5-HT1A/5-HT7 receptors. Antidepressant activities of the compounds in vivo were screened using the forced swimming test (FST). The results indicated that the compound 8j exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, ki = 0.84 nM; 5-HT7, ki = 12 nM) coupling with moderate 5-HT reuptake inhibitory activity (RUI, IC50 = 100 nM) and showed a marked antidepressant-like activity in the FST model.


Assuntos
Antidepressivos/síntese química , Piperazinas/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Inibidores de Captação de Serotonina/síntese química , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Células HEK293 , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/metabolismo , Atividade Motora/efeitos dos fármacos , Piperazinas/metabolismo , Piperazinas/farmacologia , Ratos , Receptor 5-HT1A de Serotonina/química , Receptores de Serotonina/química , Inibidores de Captação de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 123: 332-353, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27487565

RESUMO

A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Piperazinas/química , Receptores de Superfície Celular/metabolismo , Amidas/efeitos adversos , Amidas/farmacocinética , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Cognição/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Piperazina , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Nanoscale ; 8(11): 6094-100, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26932298

RESUMO

On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems. Herein we report the development of gadolinium arsenite nanoparticles as a self-delivery platform to store, deliver and release arsenic trioxide (ATO, Trisenox), a clinical anti-cancer drug. Specifically, unloading of the small molecule drug is triggered by an endogenous stimulus: inorganic phosphate (Pi) in the blood, fluid, and soft or hard tissue. Kinetics in vitro demonstrated that ATO is released with high ON/OFF specificity and no leakage was observed in the silent state. The nanoparticles induced tumor cell apoptosis, and reduced cancer cell migration and invasion. Plasma pharmacokinetics verified extended retention time, but no obvious disturbance of phosphate balance. Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug. These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors.


Assuntos
Antineoplásicos/química , Arsenicais/química , Sistemas de Liberação de Medicamentos , Óxidos/química , Fosfatos/química , Animais , Apoptose , Trióxido de Arsênio , Linhagem Celular Tumoral , Movimento Celular , Dextranos/química , Feminino , Células Hep G2 , Humanos , Cinética , Neoplasias Hepáticas/patologia , Camundongos , Microscopia Eletrônica de Transmissão , Nanopartículas , Invasividade Neoplásica , Transplante de Neoplasias , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica
11.
Eur J Med Chem ; 86: 219-34, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25164761

RESUMO

A series of aralkyl diamine derivatives were designed, synthesized, and evaluated for their triple reuptake inhibitory abilities. Compounds 18c (5-HT, NE, DA, IC50 = 389, 69, 238 nM), 36a (5-HT, NE, DA, IC50 = 378, 477, 247 nM), and 36d (5-HT, NE, DA, IC50 = 501, 206, 357 nM) showed in vivo activities in the rat forced swim test at 5, 10, and 20 mg/kg PO. 36a was identified as the most promising candidate in this study. Specifically, 36a exhibited high selectivity for monoamine transporters over a number of CNS-related targets. Furthermore, 36a showed a good pharmacokinetic properties and acceptable safety profile in preclinical studies.


Assuntos
Diaminas/farmacologia , Dopamina/metabolismo , Norepinefrina/antagonistas & inibidores , Serotonina/metabolismo , Animais , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Norepinefrina/metabolismo , Ratos , Relação Estrutura-Atividade
12.
Oncol Lett ; 8(2): 891-897, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25009663

RESUMO

Metastasis-associated in colon cancer 1 (MACC1) is a newly identified gene that has been shown to promote tumor cell invasion and metastasis. The present study investigated the effect of MACC1 downregulation on the biological characteristics of the ovarian cancer OVCAR3 cell line. In this study, MACC1 expression was blocked using the RNA interference technique. The downregulation of MACC1 mRNA and protein expression was confirmed using quantitative polymerase chain reaction and western blot analysis. The proliferative activity and adhesion rate of the cells were detected using cell counting kit-8 and a cell adhesion assay, while cell invasion was determined using a Matrigel invasion assay and migration capacity was observed using migration and wound-healing assays. A tube formation assay was also used to examine the angiogenic capacity of cells, and a luciferase assay was performed to assess whether MACC1 binds to the c-MET gene. The MACC1 mRNA and protein expression levels were significantly downregulated using sequence-specific small interfering RNA (siRNA). The inhibition of MACC1 expression markedly decreased the invasive, metastatic and angiogenic capacities of the cells, but only slightly inhibited growth and adhesion. In addition, a putative MACC1-binding site was identified in the 3'-untranslated region of c-MET. MACC1-siRNA was also found to significantly reduce the expression of the c-MET protein and a luciferase reporter assay confirmed that c-MET was the target gene of MACC1. These results demonstrated that the attenuation of MACC1 suppresses cell invasion and migration and that MACC1 may regulate cell metastasis through targeting the expression of c-MET. Inhibition of the function of MACC1 may represent a new strategy for treating ovarian cancer.

13.
Acta Pharmacol Sin ; 34(9): 1149-55, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23892272

RESUMO

AIM: SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine) is an atypical dopamine receptor-1 (D1 receptor) agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo. METHODS: Human serotonin transporter (SERT), norepinephrine transporters (NET) or dopamine transporters (DAT) were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [(3)H]-serotonin, [(3)H]-norepinephrine or [(3)H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 (2-8 mg/kg) were intraperitoneally injected 30 min before the tests. RESULTS: SKF83959 was a competitive inhibitor of SERT (K(i)=1.43±0.45 µmol/L), but a noncompetitive inhibitor of NET (K(i)=0.60±0.07 µmol/L) and DAT (K(i)=9.01±0.80 µmol/L). In contrast, DOV21947 was a competitive inhibitor of SERT (K(i)=0.89±0.24 µmol/L) and DAT (K(i)=1.47±0.31 µmol/L) and a noncompetitive inhibitor of NET (K(i)=0.18±0.04 µmol/L). In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner. CONCLUSION: SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.


Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Antidepressivos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Serotonina , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Células CHO , Cricetinae , Cricetulus , Depressão/tratamento farmacológico , Depressão/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
14.
Sci Rep ; 3: 1245, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23409236

RESUMO

Magnetoelectric multiferroics are materials that have coupled magnetic and electric dipole orders, which can bring novel physical phenomena and offer possibilities for new device functions. In this report, single-crystalline Bi(4.2)K(0.8)Fe(2)O(9+δ) nanobelts which are isostructural with the high-temperature superconductor Bi(2)Sr(2)CaCu(2)O(8+δ) are successfully grown by a hydrothermal method. The regular stacking of the rock salt slabs and the BiFeO(3)-like perovskite blocks along the c axis of the crystal makes the Bi(4.2)K(0.8)Fe(2)O(9+δ) nanobelts have a natural magnetoelectric-dielectric superlattice structure. The most striking result is that the bulk material made of the Bi(4.2)K(0.8)Fe(2)O(9+δ) nanobelts is of multiferroicity near room temperature accompanied with a structure anomaly. When an external magnetic field is applied, the electric polarization is greatly suppressed, and correspondingly, a large negative magnetocapacitance coefficient is observed around 270 K possibly due to the magnetoelectric coupling effect. Our result provides contributions to the development of single phase multiferroics.

15.
Yao Xue Xue Bao ; 47(6): 755-63, 2012 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-22919723

RESUMO

Compounds with serotonin reuptake inhibition/5-HT(1A) dual activity were used to build 3D pharmacophore model as a training molecules by Discover Studio. Based on the model, 8 novel aryl piperazine benzo[b][1,4] oxazine derivatives were designed and synthesized, and their structures were confirmed by 1H NMR and HR-MS. Biological evaluation illustrated that compounds VI(1) and VI(7) showed potent functional activities at both 5-HT transporter and 5-HT(1A) receptor, which can be used as lead compounds to guide future research of design and synthesis of potent novel compounds.


Assuntos
Desenho de Fármacos , Oxazinas/síntese química , Piperazinas/síntese química , Animais , Células CHO , Cricetinae , Cricetulus , Vetores Genéticos , Estrutura Molecular , Oxazinas/química , Oxazinas/farmacologia , Piperazina , Piperazinas/química , Piperazinas/farmacologia , Plasmídeos , Ligação Proteica , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/metabolismo , Relação Estrutura-Atividade , Transfecção
16.
Eur J Med Chem ; 54: 123-36, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22608762

RESUMO

A series of arylalkanol-piperidine derivatives was synthesized, and their triple reuptake inhibition and in vivo activities have been evaluated. Among them, compounds 2a, 2j, 2k, 2m and 2n exhibited high potency for 5-HT, NA and DA transporters. Optimized compounds 2j and 2m showed significant reduction of immobility time compared to that of vehicle in the mouse tail suspension test (TST) test at doses ranging from 10 to 50 mg/kg po, and were not generally motor stimulants at 50 mg/kg dose. In addition, compounds 2j and 2m displayed desirable pharmacokinetic properties in SD rats.


Assuntos
Antidepressivos/química , Antidepressivos/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacocinética , Técnicas de Química Sintética , Masculino , Camundongos , Inibidores da Captação de Neurotransmissores/metabolismo , Inibidores da Captação de Neurotransmissores/farmacocinética , Piperidinas/metabolismo , Piperidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Amina Biogênica/metabolismo
17.
Yao Xue Xue Bao ; 47(11): 1511-6, 2012 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-23387085

RESUMO

To explore novel non-opioid analgesic agents, 16 compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. YX0611-1 was treated as the leading compound. The results of mice writhing model and hot plate model showed that compounds 2, 7, 8, 9, 11 and 15 had obvious analgesic activities in vivo. The test of affinity to mu, delta, kappa receptor displayed that active compounds didn't act on opioid receptor. The results of preliminary toxicity and pharmacokinetic tests showed that compound 7 had better safety and pharmacokinetic properties than that of YX0611-1, and it deserved further development.


Assuntos
Analgésicos não Entorpecentes/síntese química , Piperazinas/síntese química , Analgésicos não Entorpecentes/química , Analgésicos não Entorpecentes/farmacocinética , Analgésicos não Entorpecentes/farmacologia , Analgésicos não Entorpecentes/toxicidade , Animais , Feminino , Masculino , Camundongos , Medição da Dor , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piperazinas/toxicidade , Distribuição Aleatória , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
18.
Yao Xue Xue Bao ; 45(3): 324-9, 2010 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-21351508

RESUMO

To explore novel monoamine reuptake inhibitor with antidepressant activity, a series of substituted aryl alkanol piperidine derivatives were designed and synthesized. All of them were new compounds, and their structures were confirmed with 1H NMR and HR-MS. The results showed that compounds 4, 5 and 8 displayed strong 5-HT, NA and DA reuptake inhibiting activities in vitro. Among the tested compounds, 4, 5 and 13 exhibited potent antidepressant activities in the mice forced swimming test. Compounds 4 and 5 have potent antidepressant activities and are worth further development.


Assuntos
Antidepressivos/síntese química , Antidepressivos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Antidepressivos/química , Dopamina/metabolismo , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Piperidinas/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Relação Estrutura-Atividade , Natação , Sinaptossomos/metabolismo
19.
Yao Xue Xue Bao ; 44(6): 603-8, 2009 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-19806890

RESUMO

To explore novel histone deacetylase (HDACs) inhibitors with anti-tumor activity, MS-275, a HDACs inhibitor, was prepared and used as a lead compound to design new N-substituted benzamide derivatives. MS-275 and eleven target compounds were obtained, and their structures were confirmed by 1H NMR and HR-MS individually. The results showed that the activity of compound 9d was equal to MS-275 in HDACs inhibition tests in vitro and worthy of further investigation. Compound 5c, 5d and 9c displayed obvious dose-effect relationship, which possessed moderate HDACs inhibitory activities. Ten compounds except 9e had selective inhibitory activities on Hut78.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Antineoplásicos/química , Benzamidas/química , Linhagem Celular Tumoral , Humanos
20.
Yao Xue Xue Bao ; 44(4): 371-8, 2009 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-19545054

RESUMO

A series of aralkyl-ketone-4-piperidol derivatives were synthesized and tested for their analgesic activities. All of the novel 30 compounds were prepared from 4-piperidone and alpha-halo-aralkyl-ketone through five steps, including Boc protection, nucleophilic addition in presence of CeCl3/NaI catalyst, deprotection, condensation and salification. Their structures were confirmed by 1H NMR and HRMS. Preliminary in vivo pharmacological trials showed that most of the synthesized compounds revealed analgesic effects. Among the tested compounds, 8, 13 and 22 exhibited potent analgesic activities in both mice writhing and mice hot plate model. The three compounds have low affinity for mu, delta, kappa receptors, which is a chance to find a better precursor of non-opioid analgesic for further optimization.


Assuntos
Analgésicos não Entorpecentes/síntese química , Limiar da Dor/efeitos dos fármacos , Piperidonas/síntese química , Analgésicos não Entorpecentes/química , Analgésicos não Entorpecentes/farmacologia , Animais , Camundongos , Estrutura Molecular , Medição da Dor , Piperidonas/química , Piperidonas/farmacologia , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
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