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1.
J Enzyme Inhib Med Chem ; 32(1): 659-671, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28274151

RESUMO

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-ß (Aß) lowering effects (51.9% decrease of Aß42) superior to phenserine (31% decrease of total Aß) in SH-SY5Y-APP695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.


Assuntos
Amiloide/biossíntese , Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Descoberta de Drogas , Meptazinol/farmacologia , Amiloide/metabolismo , Animais , Carbamatos/administração & dosagem , Carbamatos/química , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Cinética , Masculino , Meptazinol/administração & dosagem , Meptazinol/química , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Bioorg Med Chem ; 23(13): 3110-8, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26025073

RESUMO

The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-ß (Aß) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aß self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Melatonina/análogos & derivados , Meptazinol/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Acetilcolinesterase/química , Antioxidantes/síntese química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Desenho de Fármacos , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Estresse Oxidativo , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/prevenção & controle , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/química
3.
Biomed Chromatogr ; 28(6): 868-74, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24861756

RESUMO

A new cationic ß-cyclodextrin derivative, mono-6-deoxy-6-piperdine-ß-cyclodextrin (PIP-ß-CD), was synthesized and applied as a chiral selector for the enantioseparation of meptazinol and its three intermediate enantiomers (intermediates II-IV) in capillary electrophoresis. When PIP-ß-CD was employed as the single CD system, intermediate II was baseline enantioseparated while the results for the other analytes were less satisfactory. In order to enhance the selectivity and resolution of meptazinol intermediate III and intermediate IV, dual CD systems of PIP-ß-CD in combination with three different neutral CDs were synthesized and tested: ß-cyclodextrin (ß-CD), trimethyl-ß-cyclodextrin (TM-ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). After investigating the effect on the enantioseparation efficiency of the nature and the concentration of both CDs, the dual CD system consisting of PIP-ß-CD and HP-ß-CD was shown to be the most efficient for the simultaneous enantioseparation of meptazinol intermediates III and IV.


Assuntos
Analgésicos Opioides/isolamento & purificação , Ciclodextrinas/química , Eletroforese Capilar/métodos , Meptazinol/isolamento & purificação , Analgésicos Opioides/química , Eletroforese Capilar/instrumentação , Meptazinol/química , Estrutura Molecular , Estereoisomerismo
4.
J Pharm Biomed Anal ; 96: 156-61, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-24747147

RESUMO

In this paper a simple and sensitive method for determination of a novel phenylcarbamate AChE inhibitor, meserine, in mouse plasma, brain and rat plasma was evaluated using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Separation was achieved on an Alltech Alltima-C18 column (150mm×2.1mm, 3µm, Deerfield, IL, USA) with isocratic elution at a flow rate of 0.35ml/min. Detection was performed under the multiple reaction monitoring (MRM) mode using an electrospray ionization (ESI) in the positive ion mode. The protein precipitation and liquid-liquid extraction methods were used for the pretreatment of plasma and brain homogenates, respectively. The calibration curves of meserine showed good linearity over the concentration range of 0.5-1000ng/ml for mouse and rat plasma and 0.5-500ng/ml for mouse brain. The intra- and inter-day precision were less than 9.34% and the accuracy was from 95.34% to 107.78% for QC samples. The validated method was successfully applied to a preclinical pharmacokinetic study of meserine in mice and rats after intravenous and subcutaneous administration. The results showed that this novel drug could easily cross the blood-brain barrier to reach the site of drug action. Meserine was rapidly absorbed with a high subcutaneous absolute bioavailability (>90%).


Assuntos
Inibidores da Colinesterase/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Meptazinol/análogos & derivados , Fenilcarbamatos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Intravenosa , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Inibidores da Colinesterase/administração & dosagem , Humanos , Injeções Subcutâneas , Extração Líquido-Líquido , Masculino , Meptazinol/administração & dosagem , Meptazinol/farmacocinética , Camundongos , Fenilcarbamatos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/métodos , Distribuição Tecidual
5.
Anal Bioanal Chem ; 406(14): 3451-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24756818

RESUMO

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 × 100 mm, 3.5 µm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 µL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 ± 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-∞) = 283.1 ± 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/efeitos dos fármacos , Cromatografia Líquida , Meptazinol/análogos & derivados , Fenilcarbamatos/análise , Fenilcarbamatos/farmacocinética , Espectrometria de Massas em Tandem , Animais , Área Sob a Curva , Encéfalo/metabolismo , Calibragem , Química Farmacêutica/métodos , Feminino , Formiatos/química , Masculino , Meptazinol/análise , Meptazinol/farmacocinética , Camundongos , Fenilcarbamatos/química , Controle de Qualidade , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Temperatura , Distribuição Tecidual
6.
Biomed Chromatogr ; 28(1): 135-41, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23893795

RESUMO

A new capillary electrophoresis (CE) method using carboxymethyl-ß-cyclodextrin (CM-ß-CD) as chiral selector has been developed for the enantiomeric separation of meptazinol and its three intermediate enantiomers (intermediates II-IV), and validated for the application of quantitative determination of meptazinol in tablets. The primary factors affecting the separation efficiency, which include the chiral selector and its concentration, the buffer pH and composition, the organic modifiers used, and the applied voltage, were optimized. Baseline and satisfactory separations were obtained for meptazinol and its three intermediate enantiomers. For quantitative analysis of meptazinol, the method was performed at the condition using 2.0 mmol/L CM-ß-CD in 20 mmol/L H3 PO4 buffer adjusted to a pH of 6.00 with an applied voltage of 15 kV and containing 5% acetonitrile. After validation of the method in terms of its linearity, limits of detection and quantitation, accuracy, precision and selectivity, the method was successfully applied to the quantitation of meptazinol in pharmaceutical formulations.


Assuntos
Eletroforese Capilar/métodos , Meptazinol/química , Adsorção , Química Farmacêutica , Concentração de Íons de Hidrogênio , Meptazinol/isolamento & purificação , Estereoisomerismo , beta-Ciclodextrinas/química
7.
CNS Neurosci Ther ; 20(2): 165-71, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24279603

RESUMO

AIMS: To investigate whether Meserine, a novel phenylcarbamate derivative of (-)-meptazinol, possesses beneficial activities against cholinergic deficiency and amyloidogenesis, the two major pathological characteristics of Alzheimer's disease (AD). METHODS: Ellman's assay and Morris water maze were used to detect acetylcholinesterase (AChE) activity and evaluate spatial learning and memory ability, respectively. Both high content screening and Western blotting were carried out to detect ß-amyloid precursor protein (APP), while RT-PCR and ELISA were conducted to detect APP-mRNA and ß-amyloid peptide (Aß). RESULTS: In scopolamine-induced dementia mice, Meserine (1 mg/kg, i.p.) significantly ameliorated spatial learning and memory deficits, which was consistent with its in vitro inhibitory ability against AChE (recombinant human AChE, IC50 = 274 ± 49 nM). Furthermore, Meserine (7.5 mg/kg) injected intraperitoneally once daily for 3 weeks lowered APP level by 28% and Aß42 level by 42% in APP/PS1 transgenic mouse cerebrum. This APP modulation action might be posttranscriptional, as Meserine reduced APP by about 30% in SH-SY5Y-APP695 cells but did not alter APP-mRNA level. And both APP and Aß42 lowering action of Meserine maintained longer than that of rivastigmine. CONCLUSION: Meserine executes dual actions against cholinergic deficiency and amyloidogenesis and provides a promising lead compound for symptomatic and modifying therapy of AD.


Assuntos
Amiloidose/tratamento farmacológico , Amiloidose/genética , Demência/induzido quimicamente , Demência/tratamento farmacológico , Meptazinol/análogos & derivados , Fenilcarbamatos/uso terapêutico , Escopolamina , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Linhagem Celular Tumoral , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Meptazinol/farmacologia , Meptazinol/uso terapêutico , Camundongos , Camundongos Transgênicos , Neuroblastoma/patologia , Fenilcarbamatos/farmacologia , Presenilina-1/genética , RNA Mensageiro/metabolismo
8.
Pharmacol Biochem Behav ; 104: 138-43, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23262302

RESUMO

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder which is characterized by the progressive deterioration of cognition and the emergence of behavioral and psychological symptoms in aging patients. Given that the clinical effectiveness of acetylcholinesterase inhibitors (AChEIs) has still been questioned due to dubious disease-modifying effects, the multi-target directed ligand (MTDL) design has become an emerging strategy for developing new drugs for AD treatment. Bis(9)-(-)-nor-meptazinol (Bis-Mep) was firstly reported by us as a novel MTDL for both potent cholinesterase and amyloid-ß aggregation inhibition. In this study, we further explored its AChE inhibition kinetic features and cognitive amelioration. Bis-Mep was found to be a mixed-type inhibitor on electric eel AChE by enzyme kinetic study. Molecular docking revealed that two "water bridges" located at the two wings of Bis-Mep stabilized its interaction with both catalytic and peripheral anionic sites of AChE. Furthermore, subcutaneous administration of Bis-Mep (10, 100 or 1000 ng/kg) significantly reversed the scopolamine-induced memory deficits in a typical bell-shaped dose-response manner. The maximal cognitive amelioration of Bis-Mep was achieved at 100 ng/kg, comparable with the effect of a reference drug Huperzine A at 1 mg/kg and also the relevant AChE inhibition in brain. These findings suggested that Bis-Mep might be a promising dual-binding AChE inhibitor for potential AD therapeutics.


Assuntos
Inibidores da Colinesterase/farmacologia , Transtornos da Memória/tratamento farmacológico , Meptazinol/análogos & derivados , Nootrópicos/farmacologia , Escopolamina/toxicidade , Acetilcolinesterase/química , Alcaloides/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Inibidores da Colinesterase/química , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Cinética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Meptazinol/química , Meptazinol/farmacologia , Camundongos , Modelos Moleculares , Nootrópicos/química , Sesquiterpenos/administração & dosagem
9.
Toxicol Appl Pharmacol ; 264(1): 65-72, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22842334

RESUMO

The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(-)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC(50) values of 9.63µM (for ZLA) and 8.64µM (for ZLB), and prevent AChE-induced amyloid-ß (Aß) aggregation with IC(50) values of 49.1µM (for ZLA) and 55.3µM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aß aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Meptazinol/análogos & derivados , Meptazinol/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Sítios de Ligação , Quelantes/administração & dosagem , Quelantes/química , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/química , Cobre/metabolismo , Humanos , Concentração Inibidora 50 , Meptazinol/administração & dosagem , Camundongos , Zinco/metabolismo
10.
J Anal Toxicol ; 36(1): 69-73, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22290756

RESUMO

Meptazinol (Meptid(®)) is an analgesic drug that is used to treat mild to moderate pain including postoperative pain, obstetrical pain, and the pain of renal colic. This case reports a death due to the combined effects of meptazinol and alcohol in a man with significant heart disease and alcoholic liver disease. A 57-year-old male was found unresponsive in his bed at home with empty blister packets of meptazinol around him. A general drug screen detected the presence of meptazinol, and caffeine and metabolites, in cardiac blood. Analysis, both quantitative (HPLC-DAD) and qualitative (HPLC-DAD, LC-MS), of meptazinol was carried out. Meptazinol was found at the following concentrations: 15.5 mg/L in unpreserved femoral blood; 18.6 mg/L in preserved (fluoride-oxalate) femoral blood; 52.1 mg/L in unpreserved cardiac blood; 16.8 mg/L in preserved vitreous; 61.7 mg/L in unpreserved urine; and 9.8 g/L in stomach contents. Ethanol, analyzed by headspace GC-FID, was present in preserved (fluoride-oxalate) femoral venous blood, urine, and vitreous at concentrations of 232 mg/100 mL, 297 mg/100 mL, and 192 mg/100 mL, respectively. Death was attributed to meptazinol and ethanol toxicity, with atherosclerotic coronary artery disease as a contributing factor.


Assuntos
Etanol/envenenamento , Meptazinol/envenenamento , Cromatografia Líquida de Alta Pressão , Evolução Fatal , Humanos , Masculino , Meptazinol/farmacocinética , Pessoa de Meia-Idade
11.
J Chromatogr B Analyt Technol Biomed Life Sci ; 881-882: 126-30, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22204875

RESUMO

A rapid, simple and sensitive LC-MS/MS method was developed and validated for the determination of Bis(9)-(-)-Meptazinol (B9M) in rat plasma. Protein precipitation method was used for sample preparation, using five volumes of methanol as the precipitation agent. The analytes were separated by a Zorbax Extend-C18 column with the mobile phase of methanol-water (containing 5mM ammonium formate, pH 9.8) (95:5, v/v), and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. Retention time of IS (Bis(5)-(-)-Meptazinol) and B9M were 1.9 min and 3.3 min, respectively. The limit of detection was 0.1 ng/ml and the linear range was 1-500 ng/ml. The relative standard deviation (RSD) of intra-day and inter-day variation was 4.4-6.2% and 6.2-8.9%, respectively. The extraction recoveries of B9M in plasma were over 95%. The method proved to be applicable to the pharmacokinetic study of B9M in rat after intravenous and subcutaneous administration.


Assuntos
Inibidores da Colinesterase/sangue , Cromatografia Líquida de Alta Pressão/métodos , Meptazinol/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Doença de Alzheimer/sangue , Doença de Alzheimer/tratamento farmacológico , Animais , Área Sob a Curva , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacocinética , Feminino , Injeções Intravenosas , Injeções Subcutâneas , Limite de Detecção , Modelos Lineares , Masculino , Meptazinol/administração & dosagem , Meptazinol/sangue , Meptazinol/farmacocinética , Metanol , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
12.
Anaesthesist ; 60(11): 995-1001, 2011 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-21918824

RESUMO

OBJECTIVE: Epidural regional analgesia is still recommended as the gold standard for obstetric analgesia due to its high efficacy and less depressing effects to the central nervous system. However, if absolute or relative contraindications for a regional anesthetic technique are present, there is a need for an effective and safe alternative. This survey investigates the current use of intravenous opioids, with a focus on remifentanil as patient-controlled intravenous analgesia (PCIA), in obstetrics in German hospitals. METHODS: A questionnaire was sent to 930 anesthesia units. Data were collected and analyzed using SPSS statistical package (PASW Statistics 18.0). The questionnaire requested statistics on births, the existing alternative labor analgesic techniques, intramuscular or intravenous opioids, PCIA or other options. Furthermore, the questions focused on details regarding the use of intravenous opioids in conjunction with PCIA techniques. RESULTS: Replies were received from 343 anesthetic departments (response rate 37%) and 281 clinics had an obstetric department and were included for further analysis. All clinics provided a 24 h epidural service and the most commonly used opioids were pethidine (19%), meptazinol (17%) and piritramide (16%) for intermittent intravenous/intramuscular administration. Only 0.9% of the clinics offered nitrous oxide as an alternative analgesic technique and 22 (8%) of the responding anesthetic departments offered PCIA. Remifentanil was the most popular choice in conjunction with PCIA (68%) for labor analgesia. Most hospitals offering PCIA continuously monitor oxygen saturation (91%) and the blood pressure (95%), whereas continuous electrocardiograms (18%) and clinical observation of the respiratory frequency (19%) were less commonly reported. However, most clinics offered one-to-one nursing for the parturient using an opioid PCIA. CONCLUSIONS: This survey revealed that pethidine, meptazinol and piritramide are the most common opioids for opioid-based systemic labor pain relief in Germany. If PCIA is offered, remifentanil is the most popular opioid. However, only a few clinics are routinely using PCIA for obstetric analgesia. Furthermore the study showed that the current monitoring standards seem to have room for improvement with respect to safe administration of an opioid PCIA. The safety standards require continuous observation of the oxygen saturation, the possibility for oxygen supply, one-to-one nursing for a close clinical observation of the mother and the presence of an anesthetist during the initial titration phase to safely apply this technique. Applying these safety standards PCIA may prove a useful alternative for central neuraxial labor analgesia in those women who either do not want, cannot have or do not need epidural analgesia.


Assuntos
Analgesia Obstétrica/métodos , Analgésicos Opioides , Piperidinas , Adulto , Analgesia Epidural , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Uso de Medicamentos , Eletrocardiografia , Feminino , Alemanha , Pesquisas sobre Serviços de Saúde , Humanos , Meperidina/administração & dosagem , Meptazinol , Monitorização Fisiológica , Oxigênio/sangue , Piperidinas/administração & dosagem , Pirinitramida/administração & dosagem , Gravidez , Remifentanil , Inquéritos e Questionários
13.
J Chromatogr B Analyt Technol Biomed Life Sci ; 877(30): 3787-91, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19819764

RESUMO

A robust and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with positive electrospray ionization (ESI) was developed for the determination of hydrochloride meptazinol in human plasma. After liquid-liquid extraction of 200mul of human plasma, HPLC separation was achieved on a Thermo Hypurity Cyano column, using acetonitrile:ammonium formate (50mM, aq) (70:30, v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 234-->234 for meptazinol and m/z 152-->110 for the IS (acetaminophen), respectively. The calibration curves were linear over the range of 0.2925-292.5ng/ml, with the limit of quantification (LOQ) 0.2925ng/ml. The mean absolute recovery of hydrochloride meptazinol was more than 70.21%. Intra- and inter-day precisions were less than 9.05% and 12.89%, respectively. And the accuracy was within -2.99% to 4.96%. This method was applied to a pharmacokinetic study of hydrochloride meptazinol tablets in healthy Chinese volunteers.


Assuntos
Cromatografia Líquida/métodos , Meptazinol/sangue , Meptazinol/urina , Espectrometria de Massas por Ionização por Electrospray/métodos , Analgésicos Opioides/sangue , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/urina , Feminino , Humanos , Masculino , Meptazinol/farmacocinética
14.
J Med Chem ; 52(8): 2543-9, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19326912

RESUMO

A bis-(-)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Abeta peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the "anionic" subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440N(epsilon2), which is hydrogen-bonded to Ser200O(gamma) in the native enzyme. The second nor-meptazinol binds at the peripheral "anionic" site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(-)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.


Assuntos
Acetilcolinesterase/química , Meptazinol/análogos & derivados , Meptazinol/química , Modelos Moleculares , Animais , Domínio Catalítico , Cristalografia por Raios X , Ligação de Hidrogênio , Camundongos , Estrutura Molecular , Torpedo
15.
J Med Chem ; 51(7): 2027-36, 2008 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-18333606

RESUMO

Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Meptazinol/análogos & derivados , Meptazinol/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/efeitos dos fármacos , Peptídeos beta-Amiloides/química , Animais , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Meptazinol/síntese química , Meptazinol/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Testes de Toxicidade
16.
Eur J Anaesthesiol ; 24(1): 53-8, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16834791

RESUMO

BACKGROUND AND OBJECTIVE: To evaluate the different potencies of several opioids in obtunding reflex mechanisms of laryngoscopy and intubation. METHODS: Three groups of patients (each n = 25, ASA 1-2) undergoing elective plastic surgery were randomly given meptazinol (2.5 mg kg-1), nalbuphine (0.3 mg kg-1) or fentanyl (5 microg kg-1) in a blinded fashion prior to laryngoscopy and intubation. This was followed by a standardized bolus induction of a barbiturate and a muscle relaxant. The response to laryngoscopy and intubation was studied, using blood pressure, heart rate and bispectral index. RESULTS: With fentanyl, there was an increase of heart rate by 17%, and systolic blood pressure by 7% when compared to control. Bispectral index dropped an additional 8% when compared to 1 min after barbiturate induction. In the nalbuphine group there was a 16% increase in systolic blood pressure, and a 16% increase in heart rate when compared to control. Also, bispectral index increased by 18% when compared to 1 min after barbiturate injection. The group receiving meptazinol demonstrated no cardiovascular changes although bispectral index dropped by an additional 19% when compared to 1 min after barbiturate injection. CONCLUSION: Meptazinol, appears to depress cardiovascular stimulatory effects and electroencephalogram arousal induced by laryngoscopy and intubation better than nalbuphine or fentanyl.


Assuntos
Fentanila/farmacologia , Intubação , Laringoscopia , Meptazinol/farmacologia , Nalbufina/farmacologia , Adolescente , Adulto , Vasos Coronários/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca , Humanos , Pessoa de Meia-Idade
17.
Acta Pharmacol Sin ; 27(9): 1247-52, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16923347

RESUMO

AIM: To further investigate the analgesic pharmacophore of (+)-meptazinol. METHODS: Two different opioid pharmacophores, Pharm-I and Pharm-II, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines. Two conformers of (+)-meptazinol (Conformer-I and Conformer-II) detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modeling tool kit for molecular design and analysis. RESULTS: Conformer-I fit Pharm-I from typical opiates well. However, Conformer-II fit none of these pharmacophores. Instead, it was found to be similar to another potent analgesic, benzofuro[2,3-c]pyridin-6-ol, whose pharmacophore was suggested to hold the transitional state between the two established pharmacophores. Unlike typical analgesics derived from 4-aryl piperidine (eg, meperidine) with one conformer absolutely overwhelming, the (+)-meptazinol exists in two conformers with similar amounts in solution. Furthermore, both conformers can not transform to each other freely in ordinary conditions based on our NMR results. CONCLUSION: (+)-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.


Assuntos
Analgésicos Opioides/química , Meptazinol/química , Analgésicos Opioides/farmacologia , Meptazinol/farmacologia , Conformação Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
18.
J Mol Model ; 12(4): 390-7, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16404617

RESUMO

Molecular docking has been performed to investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 A). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (-)-MEP seemed to bind with the enzyme catalytic site in an open-gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (-)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (-)-MEP as new AChE inhibitors. [Figure: see text].


Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Meptazinol/análogos & derivados , Meptazinol/química , Modelos Moleculares , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Ligantes , Meptazinol/farmacologia , Estrutura Molecular , Estrutura Terciária de Proteína , Torpedo/metabolismo
19.
Yao Xue Xue Bao ; 40(8): 754-7, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16268513

RESUMO

AIM: To investigate the extent of systemic absorption and uptake of meptazinol (MEP) hydrochloride in cerebrospinal fluid (CSF) after intranasal administration on rats and compare with oral administration. METHODS: CSF samples were collected by a serial sampling method. The concentration of MEP in the biological samples was measured by HPLC with fluorescence detector. RESULTS: Rapid and significant levels of MEP in plasma and CSF can be achieved after nasal administration whereas the oral administration resulted in considerably lower drug concentrations. AUC in plasma and CSF from the nasal route are 7.375 and 15.6 folds compared with those of the oral route, respectively. CONCLUSION: Intranasal MEP is able to show quick absorption and improve the bioavailability, which could be a promising alternative to oral administration.


Assuntos
Analgésicos Opioides/farmacocinética , Meptazinol/farmacocinética , Administração Intranasal , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Analgésicos Opioides/líquido cefalorraquidiano , Animais , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Masculino , Meptazinol/administração & dosagem , Meptazinol/sangue , Meptazinol/líquido cefalorraquidiano , Ratos , Ratos Sprague-Dawley
20.
Bioorg Med Chem Lett ; 15(22): 4953-6, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16154745

RESUMO

Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavailability. The prodrug (3) showed a 4-fold increase in oral bioavailability over the parent drug meptazinol in rats.


Assuntos
Cumarínicos/química , Desenho de Fármacos , Meptazinol/química , Meptazinol/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Animais , Disponibilidade Biológica , Meptazinol/síntese química , Estrutura Molecular , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ratos
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