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1.
Bioorg Med Chem ; 23(13): 3110-8, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-26025073

ABSTRACT

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.


Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Melatonin/analogs & derivatives , Meptazinol/analogs & derivatives , Neuroprotective Agents/pharmacology , Peptide Fragments/antagonists & inhibitors , Acetylcholinesterase/chemistry , Antioxidants/chemical synthesis , Cell Line, Tumor , Cell Membrane Permeability , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Drug Design , Humans , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/chemical synthesis , Oxidative Stress , Protein Aggregates/drug effects , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/prevention & control , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/chemistry
2.
Anal Bioanal Chem ; 406(14): 3451-8, 2014 May.
Article in English | MEDLINE | ID: mdl-24756818

ABSTRACT

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.


Subject(s)
Alzheimer Disease/metabolism , Brain/drug effects , Chromatography, Liquid , Meptazinol/analogs & derivatives , Phenylcarbamates/analysis , Phenylcarbamates/pharmacokinetics , Tandem Mass Spectrometry , Animals , Area Under Curve , Brain/metabolism , Calibration , Chemistry, Pharmaceutical/methods , Female , Formates/chemistry , Male , Meptazinol/analysis , Meptazinol/pharmacokinetics , Mice , Phenylcarbamates/chemistry , Quality Control , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization , Temperature , Tissue Distribution
3.
J Pharm Biomed Anal ; 96: 156-61, 2014 Aug 05.
Article in English | MEDLINE | ID: mdl-24747147

ABSTRACT

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%).


Subject(s)
Cholinesterase Inhibitors/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Meptazinol/analogs & derivatives , Phenylcarbamates/pharmacokinetics , Tandem Mass Spectrometry/methods , Administration, Intravenous , Animals , Biological Availability , Blood-Brain Barrier/metabolism , Brain/metabolism , Cholinesterase Inhibitors/administration & dosage , Humans , Injections, Subcutaneous , Liquid-Liquid Extraction , Male , Meptazinol/administration & dosage , Meptazinol/pharmacokinetics , Mice , Phenylcarbamates/administration & dosage , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/methods , Tissue Distribution
4.
CNS Neurosci Ther ; 20(2): 165-71, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24279603

ABSTRACT

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.


Subject(s)
Amyloidosis/drug therapy , Amyloidosis/genetics , Dementia/chemically induced , Dementia/drug therapy , Meptazinol/analogs & derivatives , Phenylcarbamates/therapeutic use , Scopolamine , Acetylcholinesterase/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Cell Line, Tumor , Cholinesterase Inhibitors/therapeutic use , Disease Models, Animal , Drug Administration Schedule , Humans , Maze Learning/drug effects , Meptazinol/pharmacology , Meptazinol/therapeutic use , Mice , Mice, Transgenic , Neuroblastoma/pathology , Phenylcarbamates/pharmacology , Presenilin-1/genetics , RNA, Messenger/metabolism
5.
Pharmacol Biochem Behav ; 104: 138-43, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23262302

ABSTRACT

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.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Memory Disorders/drug therapy , Meptazinol/analogs & derivatives , Nootropic Agents/pharmacology , Scopolamine/toxicity , Acetylcholinesterase/chemistry , Alkaloids/administration & dosage , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Alzheimer Disease/psychology , Animals , Brain/drug effects , Brain/enzymology , Cholinesterase Inhibitors/chemistry , Cognition/drug effects , Disease Models, Animal , Female , Humans , Kinetics , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Memory Disorders/psychology , Meptazinol/chemistry , Meptazinol/pharmacology , Mice , Models, Molecular , Nootropic Agents/chemistry , Sesquiterpenes/administration & dosage
6.
Toxicol Appl Pharmacol ; 264(1): 65-72, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22842334

ABSTRACT

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.


Subject(s)
Amyloid beta-Peptides/drug effects , Chelating Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Meptazinol/analogs & derivatives , Meptazinol/pharmacology , Acetylcholinesterase/drug effects , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Binding Sites , Chelating Agents/administration & dosage , Chelating Agents/chemistry , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/chemistry , Copper/metabolism , Humans , Inhibitory Concentration 50 , Meptazinol/administration & dosage , Mice , Zinc/metabolism
7.
J Chromatogr B Analyt Technol Biomed Life Sci ; 881-882: 126-30, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22204875

ABSTRACT

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.


Subject(s)
Cholinesterase Inhibitors/blood , Chromatography, High Pressure Liquid/methods , Meptazinol/analogs & derivatives , Tandem Mass Spectrometry/methods , Alzheimer Disease/blood , Alzheimer Disease/drug therapy , Animals , Area Under Curve , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/pharmacokinetics , Female , Injections, Intravenous , Injections, Subcutaneous , Limit of Detection , Linear Models , Male , Meptazinol/administration & dosage , Meptazinol/blood , Meptazinol/pharmacokinetics , Methanol , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization/methods
8.
J Med Chem ; 52(8): 2543-9, 2009 Apr 23.
Article in English | MEDLINE | ID: mdl-19326912

ABSTRACT

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.


Subject(s)
Acetylcholinesterase/chemistry , Meptazinol/analogs & derivatives , Meptazinol/chemistry , Models, Molecular , Animals , Catalytic Domain , Crystallography, X-Ray , Hydrogen Bonding , Mice , Molecular Structure , Torpedo
9.
J Med Chem ; 51(7): 2027-36, 2008 Apr 10.
Article in English | MEDLINE | ID: mdl-18333606

ABSTRACT

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.


Subject(s)
Amyloid beta-Peptides/drug effects , Cholinesterase Inhibitors/pharmacology , Meptazinol/analogs & derivatives , Meptazinol/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/drug effects , Amyloid beta-Peptides/chemistry , Animals , Binding Sites , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Drug Design , Enzyme Activation/drug effects , Humans , Meptazinol/chemical synthesis , Meptazinol/chemistry , Mice , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Toxicity Tests
10.
J Mol Model ; 12(4): 390-7, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16404617

ABSTRACT

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].


Subject(s)
Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Meptazinol/analogs & derivatives , Meptazinol/chemistry , Models, Molecular , Animals , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Crystallography, X-Ray , Inhibitory Concentration 50 , Ligands , Meptazinol/pharmacology , Molecular Structure , Protein Structure, Tertiary , Torpedo/metabolism
11.
J Chromatogr B Biomed Appl ; 663(2): 315-26, 1995 Jan 20.
Article in English | MEDLINE | ID: mdl-7735479

ABSTRACT

A reversed-phase high-performance liquid chromatographic method to separate meptazinol and its phase I metabolites has been developed using a LiChrosper 100 CN column and a mobile phase of trimethylammoniumacetate buffer (pH 5.5)-acetonitrile-methanol. Quantification of meptazinol and N-desmethylmeptazinol in biological samples was achieved by extraction with organic solvents and chromatographic analysis (detection limit 0.4 and 0.25 micrograms/ml, respectively). Afterwards the enantiomeric ratio of the two compounds was determined on a Chiral AGP column with a mobile phase of phosphate buffer (pH 7.0)-acetonitrile (alpha = 1.29 and 1.49, respectively). In-vitro metabolism data after incubation of the racemic compound and the enantiomers with liver supernatant and microsomes of different species are presented. Finally urinary data of two volunteers after oral application of the racemic drug were determined.


Subject(s)
Meptazinol/metabolism , Animals , Biotransformation , Chromatography, High Pressure Liquid , Humans , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Male , Meptazinol/analogs & derivatives , Meptazinol/pharmacokinetics , Meptazinol/urine , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Phenobarbital/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Stereoisomerism
12.
Br J Pharmacol ; 88(3): 689-95, 1986 Jul.
Article in English | MEDLINE | ID: mdl-3742156

ABSTRACT

Both (+/-)-meptazinol (2 mg kg-1) and levorphanol (1 mg kg-1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase. The individual (+)- and (-)-enantiomers of meptazinol (2 mg kg-1 i.p.) induced comparable increases in cumulative food intake. N-methyl meptazinol (2-10 mg kg-1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10-100 micrograms per animal). Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg-1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (-)-Mr 1452 but not by its (+)-enantiomer Mr 1453 which is not effective as an opioid antagonist. Intracerebroventricular administration of the delta-opioid antagonist ICI 154,129 (10 micrograms per animal) suppressed meptazinol but not levorphanol hyperphagia. It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a mu-opioid receptor mechanism common to levorphanol, and also through delta-opioid receptor mechanism(s).


Subject(s)
Azepines/pharmacology , Eating/drug effects , Meptazinol/pharmacology , Animals , Benzomorphans/pharmacology , Drug Interactions , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/pharmacology , Levorphanol/pharmacology , Male , Meptazinol/analogs & derivatives , Narcotic Antagonists/pharmacology , Rats , Rats, Inbred Strains , Stereoisomerism , Time Factors
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