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1.
Biochemistry (Mosc) ; 89(3): 507-522, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38648769

ABSTRACT

Some tricyclic antidepressants (TCAs), including amitriptyline (ATL), clomipramine (CLO), and desipramine (DES), are known to be effective for management of neuropathic pain. It was previously determined that ATL, CLO, and DES are capable of voltage-dependent blocking of NMDA receptors of glutamate (NMDAR), which play a key role in pathogenesis of neuropathic pain. Despite the similar structure of ATL, CLO, and DES, efficacy of their interaction with NMDAR varies significantly. In the study presented here, we applied molecular modeling methods to investigate the mechanism of binding of ATL, CLO, and DES to NMDAR and to identify structural features of the drugs that determine their inhibitory activity against NMDAR. Molecular docking of the studied TCAs into the NMDAR channel was performed. Conformational behavior of the obtained complexes in the lipid bilayer was simulated by the method of molecular dynamics (MD). A single binding site (upper) for the tertiary amines ATL and CLO and two binding sites (upper and lower) for the secondary amine DES were identified inside the NMDAR channel. The upper and lower binding sites are located along the channel axis at different distances from the extracellular side of the plasma membrane. MD simulation revealed that the position of DES in the lower site is stabilized only in the presence of sodium cation inside the NMDAR channel. DES binds more strongly to NMDAR compared to ATL and CLO due to simultaneous interaction of two hydrogen atoms of its cationic group with the asparagine residues of the ion pore of the receptor. This feature may be responsible for the stronger side effects of DES. It has been hypothesized that ATL binds to NMDAR less efficiently compared to DES and CLO due to its lower conformational mobility. The identified features of the structure- and cation-dependent mechanism of interaction between TCAs and NMDAR will help in the further development of effective and safe analgesic therapy.


Subject(s)
Antidepressive Agents, Tricyclic , Molecular Docking Simulation , Molecular Dynamics Simulation , Receptors, N-Methyl-D-Aspartate , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, N-Methyl-D-Aspartate/chemistry , Antidepressive Agents, Tricyclic/pharmacology , Antidepressive Agents, Tricyclic/metabolism , Antidepressive Agents, Tricyclic/chemistry , Binding Sites , Amitriptyline/chemistry , Amitriptyline/metabolism , Amitriptyline/pharmacology , Humans , Clomipramine/pharmacology , Clomipramine/chemistry , Clomipramine/metabolism , Cations/metabolism , Cations/chemistry , Desipramine/pharmacology , Protein Binding
2.
Biomark Med ; 14(12): 1069-1084, 2020 08.
Article in English | MEDLINE | ID: mdl-32969243

ABSTRACT

Aim: To explore the mechanism of gastric carcinogenesis by mining potential hub genes and to search for promising small-molecular compounds for gastric cancer (GC). Materials & methods: The microarray datasets were downloaded from Gene Expression Omnibus database and the genes and compounds were analyzed by bioinformatics-related tools and software. Results: Six hub genes (MKI67, PLK1, COL1A1, TPX2, COL1A2 and SPP1) related to the prognosis of GC were confirmed to be upregulated in GC and their high expression was correlated with poor overall survival rate in GC patients. In addition, eight candidate compounds with potential anti-GC activity were identified, among which resveratrol was closely correlated with six hub genes. Conclusion: Six hub genes identified in the present study may contribute to a more comprehensive understanding of the mechanism of gastric carcinogenesis and the predicted potential of resveratrol may provide valuable clues for the future development of targeted anti-GC inhibitors.


Subject(s)
Gene Expression Profiling , Genes, Neoplasm , Neoplasm Proteins/genetics , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Amiodarone/chemistry , Cell Cycle Proteins/genetics , Clomipramine/chemistry , Collagen Type I/genetics , Databases, Genetic , Datasets as Topic , Gene Expression Regulation, Neoplastic , Humans , Ki-67 Antigen/genetics , Levallorphan/chemistry , Microtubule-Associated Proteins/genetics , Osteopontin/genetics , Piroxicam/chemistry , Procaine/chemistry , Procaine/pharmacology , Procaine/therapeutic use , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Resveratrol/chemistry , Resveratrol/pharmacology , Small Molecule Libraries/therapeutic use , Ursodeoxycholic Acid/chemistry , Vorinostat/chemistry , Polo-Like Kinase 1
3.
Eur J Med Chem ; 187: 111915, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-31838329

ABSTRACT

A series of 10,11-dihydro-5H-dibenzo [b,f]azepine hydroxamates (4-15) were synthesized, behaving as histone deacetylase inhibitors, and examined for their influence on vascular cognitive impairment (VCI), which correlated with dementia. The results revealed that (E)-3-(4-(((3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)propyl)amino)methyl)phenyl)-N-hydroxy-acrylamide (13) increases cerebral blood flow (CBF), attenuates cognitive impairment, and improves hippocampal atrophy in in vivo study. It is also able to increase the level of histone acetylation (H3K14 or H4K5) in the cortex and hippocampus of chronic cerebral hypoperfusion (CCH) mice; as a result, it could be a potential HDAC inhibitor for the treatment of vascular cognitive impairment.


Subject(s)
Azepines/pharmacology , Clomipramine/analogs & derivatives , Cognitive Dysfunction/drug therapy , Dementia, Vascular/drug therapy , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/pharmacology , Protective Agents/pharmacology , Animals , Azepines/chemistry , Cell Line, Tumor , Clomipramine/chemistry , Clomipramine/pharmacology , Cognitive Dysfunction/metabolism , Dementia, Vascular/metabolism , Dose-Response Relationship, Drug , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Protective Agents/chemical synthesis , Protective Agents/chemistry , Structure-Activity Relationship
4.
Nanomedicine (Lond) ; 13(17): 2139-2154, 2018 09.
Article in English | MEDLINE | ID: mdl-30129397

ABSTRACT

AIM: Pharmacologic agents that affect autophagy were tested for their abilities to enhance macrophage nanoformulated antiretroviral drug (ARV) depots and its slow release. METHODS: These agents included URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-ß-cyclodextrin (HBC) and clonidine. Each was administered with nanoformulated atazanavir (ATV) nanoparticles to human monocyte-derived macrophages. ARV retention, antiretroviral activity and nanocrystal autophagosomal formation were evaluated. RESULTS: URMC-099, HBC and clonidine retained ATV. HBC, URMC-099 and rapamycin improved intracellular ATV retention. URMC-099 proved superior among the group in affecting antiretroviral activities. CONCLUSION: Autophagy inducing agents, notably URMC-099, facilitate nanoformulated ARV depots and lead to sustained release and improved antiretroviral responses. As such, they may be considered for development as part of long acting antiretroviral treatment regimens.


Subject(s)
Anti-HIV Agents/chemistry , Atazanavir Sulfate/pharmacology , Autophagy/drug effects , Drug Carriers/chemistry , Nanoparticles/chemistry , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacology , Atazanavir Sulfate/administration & dosage , Atazanavir Sulfate/chemistry , Cell Survival/drug effects , Clomipramine/administration & dosage , Clomipramine/analogs & derivatives , Clomipramine/chemistry , Clomipramine/pharmacology , Clonidine/administration & dosage , Clonidine/chemistry , Clonidine/pharmacology , Drug Interactions , Drug Liberation , HIV-1/drug effects , Humans , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Metformin/administration & dosage , Metformin/chemistry , Metformin/pharmacology , Particle Size , Pyridines/administration & dosage , Pyridines/chemistry , Pyridines/pharmacology , Pyrroles/administration & dosage , Pyrroles/chemistry , Pyrroles/pharmacology , Sirolimus/administration & dosage , Sirolimus/chemistry , Sirolimus/pharmacology , Tissue Distribution , beta-Cyclodextrins/administration & dosage , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/pharmacology
5.
Article in English | MEDLINE | ID: mdl-28825989

ABSTRACT

The applicability of Amino-functionalized Fe3O4 nanoparticles (NPs) as an effective adsorbent was developed for the extraction and determination of clomipramine (CLP) in plasma sample by ultrasound-assisted dispersive magnetic solid phase extraction (UADM-SPE) and high-performance liquid chromatography-ultraviolet (HPLC-UV) detection. Fabrication of the Fe3O4@SiO2-NH2 magnetic nanoparticles confirmed by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The effect of different extraction parameters (i.e. pH of the sample solution, the amount of magnetic nanoparticles (MNPs), sample volume, temperature and sonication time) on the extraction recovery of CLP were investigated by response surface methodology through central composite design (CCD). The optimum condition is obtained when the affecting parameters are set to: pH of the sample solution=9, the amount of MNPs=37mg, sample volume=23mL, 25°C temperature and sonication time=1min. Under the optimum condition, extraction recovery was 90.6% with relative standard deviation of 3.5%, and enrichment factor of 117. The linear range for determination of CLP was 0.017-0.70mgL-1 with a determination coefficient (R2) of 0.999. Limit of detection (LOD) and limit of quantification (LOQ) were 0.005 and 0.0167mgL-1, respectively. The established UADM-SPE-HPLC-UV method was rapid, simple and efficient for determination of CLP in human plasma samples.


Subject(s)
Chromatography, High Pressure Liquid/methods , Clomipramine/blood , Magnetite Nanoparticles/chemistry , Solid Phase Extraction/methods , Sonication/methods , Clomipramine/chemistry , Clomipramine/isolation & purification , Humans , Limit of Detection , Linear Models , Reproducibility of Results , Research Design
6.
Bioorg Med Chem ; 23(5): 996-1010, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25661449

ABSTRACT

Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N(4),N(8)-bis(dibenzosuberyl)spermine (7), having a Ki value of 0.26µM. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR.


Subject(s)
Clomipramine/analogs & derivatives , Enzyme Inhibitors/pharmacology , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Polyamines/pharmacology , Trypanocidal Agents/pharmacology , Animals , Clomipramine/chemistry , Enzyme Inhibitors/chemistry , Mice , Molecular Docking Simulation , Polyamines/chemistry , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology
7.
Cell Death Dis ; 5: e1203, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24787015

ABSTRACT

Inhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto-ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine--a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologs of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologs might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications.


Subject(s)
Antidepressive Agents/pharmacology , Autophagy/drug effects , Enzyme Inhibitors/analysis , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays/methods , Ubiquitin-Protein Ligases/antagonists & inhibitors , Binding Sites , Cell Line, Tumor , Clomipramine/analogs & derivatives , Clomipramine/chemistry , Clomipramine/pharmacology , Drug Synergism , Humans , Models, Molecular , Protein Structure, Tertiary , Reproducibility of Results , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/chemistry , Ubiquitin-Protein Ligases/metabolism
8.
J Fluoresc ; 23(3): 533-42, 2013 May.
Article in English | MEDLINE | ID: mdl-23456417

ABSTRACT

Amitriptyline.HCl (AMI) and clomipramine.HCl (CMI) react with eosin Y (EY) in pH 3.8 NaAc-AcH buffer solution to form ion association complex which results in quenching of fluorescence of EY and appearance of a new resonance Rayleigh scattering (RSS) spectrum at 620 nm. The spectral characteristics of absorption, fluorescence and RSS spectra have been investigated. The factors influencing the reaction were studied and optimum conditions for the reaction have been determined. Based on fluorescence quenching, a simple and sensitive spectrofluorimetric method for determination of AMI and CMI has been developed. The fluorescence quenching intensity was measured at 550 nm using an excitation wavelength of 310 nm. The calibration graph was found to be rectilinear in the range 0.08-2.0 µg mL(-1) with detection limit of 0.017 µg mL(-1) for AMI and 0.06-2.0 µg mL(-1) with detection limit of 0.015 µg mL(-1) for CMI. The method can be satisfactorily applied to the determination of AMI and CMI in tablets without interference from commonly occurring exicipients. The recovery and RSD values obtained indicate good accuracy and precision of the method. The mechanism of the reaction and fluorescence quenching has also been discussed.


Subject(s)
Amitriptyline/analysis , Amitriptyline/chemistry , Clomipramine/analysis , Clomipramine/chemistry , Eosine Yellowish-(YS)/chemistry , Fluorescent Dyes/chemistry , Absorption , Buffers , Calibration , Drug Compounding , Hydrogen-Ion Concentration , Indicators and Reagents/chemistry , Kinetics , Osmolar Concentration , Spectrometry, Fluorescence , Temperature
9.
Crit Rev Eukaryot Gene Expr ; 22(3): 197-203, 2012.
Article in English | MEDLINE | ID: mdl-23140161

ABSTRACT

Langmuir-Blodgett (LB) technology was used to build a high-sensitivity enzyme-based biosensor for medical purposes. Recombinant fungal laccase from Rigidoporous lignosus, as previously described, was used to catalyze a widely used antidepressant in a micromolar range, namely, clomipramine. The topological properties of the laccase thin film were characterized via LB π-A isotherm and AFM (mean roughness 8.22 nm, compressibility coefficient 37.5 m/N). The sensitivity of the biosensor was investigated via UV spectroscopy, and linearity was found in the absorbance peak shift at 400 nm at drug concentration varying up to 20 uM. The enzyme kinetics was subsequently investigated with potentiometric and amperometric measurements, and we found electronic transfer of at least 1 electron, k(s) 0.57 s(-1), diffusion coefficient 3 × 10(-6) cm(2)/s, K(cat) 6825.92 min(-1), K(M) 4.1 uM, K(cat)/K(M) 2.8 × 10(7) mol(-1) s(-1), sensitivity of 440 nA/uM, maximum velocity 1706.48 nA/s, and response time less than 5 s. The amperometric and potentiometric measurements were repeated after a month, confirming the stability of the biosensor.


Subject(s)
Biosensing Techniques/methods , Laccase/chemistry , Clomipramine/blood , Clomipramine/chemistry , Electrodes , Humans , Kinetics , Laccase/genetics , Microscopy, Atomic Force/methods , Potentiometry/instrumentation , Recombinant Proteins/chemistry
10.
J Mol Graph Model ; 38: 1-12, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23079638

ABSTRACT

The dopamine transporter (DAT) facilitates the regulation of synaptic neurotransmitter levels. As a target for therapeutic and illicit psycho-stimulant drugs like antidepressants and cocaine, DAT has been studied intensively. Despite a wealth of mutational and physiological data regarding DAT, the structure remains unsolved and details of the transport mechanism, binding sites and conformational changes remain debated. A bacterial homolog of DAT, the leucine transporter (LeuT(Aa)) has been used as a template and framework for modeling and understanding DAT. Free energy profiles obtained from Multi-Configuration Thermodynamic Integration simulations allowed us to correctly identify the primary and secondary binding pockets of LeuT(Aa). A comparison of free energy profiles for dopamine and cocaine in DAT suggests that the binding site of cocaine is located in a secondary pocket, not the primary substrate site. Two recurring primary pathways for intracellular substrate release from the primary pocket are identified in both transporters using the Random Acceleration Molecular Dynamics method. One pathway appears to follow transmembranes (TMs) 1a and 6b while the other pathway follows along TMs 6b and 8. Interestingly, we observe that a single sodium ion is co-transported with leucine during both simulation types.


Subject(s)
Bacterial Proteins/chemistry , Carrier Proteins/chemistry , Cocaine/chemistry , Dopamine Plasma Membrane Transport Proteins/chemistry , Dopamine/chemistry , Leucine/chemistry , Amino Acid Sequence , Animals , Binding Sites , Biological Transport , Clomipramine/chemistry , Cocaine/metabolism , Crystallography, X-Ray , Dopamine/metabolism , Kinetics , Molecular Docking Simulation , Molecular Sequence Data , Protein Binding , Protein Structure, Tertiary , Rats , Sequence Alignment , Sodium/chemistry , Sodium/metabolism , Structural Homology, Protein , Substrate Specificity , Thermodynamics
11.
Bioorg Med Chem ; 20(1): 340-5, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22115837

ABSTRACT

Tricyclic antidepressants (TCAs), along with phenothyazines and some industrial chemicals, are shown to react with enzymes that exhibit peroxidase activity. These reactions result in the formation of reactive intermediates having unpaired electrons. The peroxidase oxidation and reactivity of two TCAs, desipramine and clomipramine, were investigated. As a model of peroxidase, horseradish peroxidase (HRP) was employed. The products of the peroxidase catalyzed oxidation of desipramine and clomipramine were identified as N-dealkylated compounds iminodibenzyl and 3-chloroiminodibenzyl using the GC/MS technique. Both drugs formed broad UV/vis absorption spectra in the presence of HRP and H(2)O(2), indicating the formation of a radical cations-reactive intermediate of the oxidation reaction. The dynamics of the formation of the desipramine intermediate was studied using UV/vis spectroscopy. The extinction coefficient was measured for the reactive intermediate, 7.80×10(3)M(-1)cm(-1), as well as the apparent Michaelis-Menten and catalytic constants, 4.4mM and 2.3s(-1), respectively. Both desipramine and clomipramine degraded DNA in the presence of HRP/H(2)O(2), as was revealed by agarose gel electrophoresis and PCI extraction. Manipulating the kinetic parameters of drug's radical formation and determining the extent of degradation to biomolecules could be potentially used for designing effective agents exhibiting specific reactivity.


Subject(s)
Antidepressive Agents/metabolism , Clomipramine/metabolism , DNA/metabolism , Desipramine/metabolism , Antidepressive Agents/chemistry , Biocatalysis , Clomipramine/chemistry , DNA/chemistry , Desipramine/chemistry , Horseradish Peroxidase/metabolism , Hydrogen Peroxide/metabolism , Kinetics , Oxidation-Reduction
12.
J Colloid Interface Sci ; 361(1): 42-8, 2011 Sep 01.
Article in English | MEDLINE | ID: mdl-21679963

ABSTRACT

The clouding behavior, i.e., formation of phase separation at elevated temperature (the temperature being known as cloud point (CP)), of three amphiphilic drugs, amitriptyline (AMT), clomipramine (CLP) and imipramine (IMP) hydrochlorides in the presence of various additives, like cationic surfactants (conventional and gemini), nonionic surfactants, bile salts, anionic hydrotropes, sodium salts of fatty acids and cyclodextrin has been investigated. These additives are generally used as drug delivery systems. The drugs used are tricyclic antidepressants. All the surfactants increase the CP of mixed micelles formed by cationic (conventional and gemini) and nonionic surfactants. Hydrotropes, bile salts and fatty acid salts, when added in low concentrations, increase the CP, whereas at high concentrations, they decrease it. ß-Cyclodextrin behaves as simple sugar and decreases the CP of the drug solutions.


Subject(s)
Amitriptyline/chemistry , Antidepressive Agents, Tricyclic/chemistry , Clomipramine/chemistry , Excipients/chemistry , Imipramine/chemistry , Bile Acids and Salts/chemistry , Cyclodextrins/chemistry , Fatty Acids/chemistry , Phase Transition , Salts/chemistry , Surface-Active Agents/chemistry , Temperature
13.
J Liposome Res ; 21(3): 194-202, 2011 Sep.
Article in English | MEDLINE | ID: mdl-20624028

ABSTRACT

The effects of tricylic antidepressant clomipramine (CLO) on the membrane properties of saturated dimyristoyl phosphatidylcholine and dipalmitoyl phosphatidylcholine as well as on unsaturated egg yolk phosphatidylcholine liposomes were investigated by the electron paramagnetic resonance spin-labeling technique, in combination with the simulation of the spectra, taking into account that the membrane is heterogeneous and composed of the regions with different fluidity characteristics. Different spin labels, monitoring membrane properties in the upper and inner parts of the membrane, were used. In general, two spectral components, having different motional characteristics, were detected in all liposomes investigated. In liposomes with saturated chains, CLO decreased the phase-transition temperature, disordered the membrane, and increased polarity in the upper part of the membrane. However, less impact was observed in liposomes with unsaturated chains. In dipalmitoyl phosphatidylcholine liposomes, it also induced molecular rearrangements near the pretransition temperature. The presence of 30 mol% cholesterol increased the fluidizing effect of CLO and modified the lateral diffusion of nitroxide in the inner part of the membrane. A unique anomalous increase in diffusion of nitroxide, dependent on CLO concentration, was detected in the temperature region where the phosphatidylcholine membrane without cholesterol experiences the phase transitions. Since the changes in the central part of the membrane were even more pronounced than in the upper part of the membrane, it could be concluded that CLO incorporates into the membrane with its hydrophobic ring parallel to the phospholipid chains.


Subject(s)
Cholesterol/chemistry , Clomipramine/chemistry , Electron Spin Resonance Spectroscopy/methods , Lipid Bilayers/chemistry , Liposomes/chemistry , Phosphatidylcholines/chemistry , Antidepressive Agents, Tricyclic/chemistry , Computer Simulation , Molecular Structure
14.
Colloids Surf B Biointerfaces ; 81(1): 152-7, 2010 Nov 01.
Article in English | MEDLINE | ID: mdl-20674295

ABSTRACT

Clomipramine hydrochloride (CLP) is an antidepressant drug which shows temperature dependent phase separation, also known as the cloud point (CP). Increase in pH decreases the CP of the drug solution. Addition of ureas/thioureas at a fixed pH (6.25) decreases/increases the CP. In ureas, presence of >CO bond causes a decrease in repulsions among positively charged drug molecules. However, >CS bond (of thioureas) behaves oppositely and hence CP increases. Cationic and non-ionic surfactants form mixed micelles and hence increase the CP. Anionic surfactants, at low concentrations, retard micellization and increase the CP. At higher concentrations, these surfactants also form mixed micelles and, due to charge opposite to the drug molecules, reduce the repulsion among micelles and act as CP suppressors. Increase in solution pH/drug concentration at different fixed concentrations of CTAB causes the CP to decrease/increase. Dye solubilization results with the drug have provided proof to the above explanation.


Subject(s)
Clomipramine/chemistry , Surface-Active Agents/chemistry , Urea/chemistry , Antidepressive Agents, Tricyclic/chemistry , Azo Compounds/chemistry , Dose-Response Relationship, Drug , Hydrogen-Ion Concentration , Molecular Structure , Solubility , Spectrophotometry , Surface-Active Agents/pharmacology , Thiourea/chemistry , Thiourea/pharmacology , Transition Temperature/drug effects , Urea/pharmacology
15.
Colloids Surf B Biointerfaces ; 64(1): 65-9, 2008 Jun 15.
Article in English | MEDLINE | ID: mdl-18291629

ABSTRACT

Conductivity measurements have been carried out on aqueous solutions of two antidepressant drugs (nortriptyline hydrochloride and clomipramine hydrochloride) with four cationic surfactants (monomeric: cetyltrimethylammonium bromide, tetradecylammonium bromide; dimeric: 1,5-pentanediyl-alpha-omega-bis(hexadecyldimethylammonium bromide), 1,4-butanediyl-alpha,omega-bis(hexadecyldimethylammonium bromide) as well as with sodium chloride. Counterions from NaCl adsorb to the charged headgroup of the drug molecules and reduce the repulsion, hence cmc decreases. cmc values decreased with the addition of surfactants indicating mixed micelle formation. Experimental mole fraction of surfactants in micelle (X1) and their ideal values (X1 id) also support this explanation. Interaction parameter, beta, and excess free energy of micellization are negative suggesting synergism in mixed state. Activity coefficients are less than unity which means non-ideal mixing.


Subject(s)
Antidepressive Agents, Tricyclic/chemistry , Clomipramine/chemistry , Electric Conductivity , Micelles , Nortriptyline/chemistry , Surface-Active Agents/chemistry , Water , Pharmaceutical Solutions
16.
J Phys Chem B ; 112(1): 168-78, 2008 Jan 10.
Article in English | MEDLINE | ID: mdl-18085762

ABSTRACT

Imipramine (IPA) and its derivatives are used widely for the treatment of depression and other mental disorders. Although there are more than 20 FDA-approved antidepressant drugs, the search continues for better compounds with fewer deleterious side effects and higher efficacy. Over the past decade, several classes of antipsychotic drugs have been developed, which-in spite of their structural diversity-share an ability to modulate neurotransmission and to produce undesirable side effects. Phototoxicity is one of the most important side effects noted in treatment with tricyclic antidepressants (TCAs), but its mechanism has not yet been elucidated. To develop new knowledge regarding the relationship between the structure and the photophysics of these TCAs, we measured the photophysical properties of IPA, desimipramine (DIPA), and clomipramine (CIPA) in different solvents. The electronic configurations for the ground and the first excited singlet states were calculated using the AM1/RHF/CI and the AM1/RHF/HE semiempirical quantum theoretical methods, respectively. The ground-state properties are solvent-independent, while the emission maxima are red-shifted with increasing solvent polarity/polarizability. However, the fluorescence quantum yield is relatively low in all of the tested solvents (phif<0.02). The primary transient intermediates produced by 266 nm high-intensity laser photolysis are the solvated electron and the corresponding radical cation, with a negligible contribution of triplet-triplet absorption. The properties determined for the primary transients generated with a 266 nm laser flash are consistent with the photodamaging effects generated through a limited radical mechanism.


Subject(s)
Clomipramine/chemistry , Imipramine/analogs & derivatives , Imipramine/chemistry , Models, Chemical , Ions/chemistry , Molecular Structure , Photochemistry , Solvents , Spectrometry, Fluorescence , Thermodynamics , Time Factors
17.
Bioorg Med Chem ; 15(24): 7765-72, 2007 Dec 15.
Article in English | MEDLINE | ID: mdl-17870537

ABSTRACT

A variety of tropane derivatives 14a-g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a-f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity.


Subject(s)
Norepinephrine Plasma Membrane Transport Proteins/metabolism , Norepinephrine/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin/pharmacology , Tropanes/chemical synthesis , 5-Hydroxytryptophan/toxicity , Adrenergic alpha-Antagonists/toxicity , Animals , Citalopram/chemical synthesis , Citalopram/chemistry , Clomipramine/chemical synthesis , Clomipramine/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Fluoxetine/chemical synthesis , Fluoxetine/chemistry , Mice , Molecular Structure , Norepinephrine Plasma Membrane Transport Proteins/drug effects , Serotonin Plasma Membrane Transport Proteins/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Tropanes/chemistry , Tropanes/pharmacology , Yohimbine/antagonists & inhibitors , Yohimbine/toxicity
18.
Electrophoresis ; 28(20): 3650-7, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17893949

ABSTRACT

CE of tricyclic antidepressants clomipramine and its metabolites demethylclomipramine, didemethylclomipramine and 8-hydroxyclomipramine resulted in partly extremely tailing peaks in bare fused-silica capillaries. Especially at high pH of the BGE this behavior was not unexpected as adsorption of the cationic analytes onto the negatively charged wall due to electrostatic attraction can be supposed. Less expected was the observation that peak tailing could not be overcome neither by using a capillary with dynamic coating with cationic CTAB added to the BGE, nor by the usage of a capillary permanently coated with polyvinyl alcohol (PVA), both operated at acidic pH. As this tailing was even more pronounced than with bare fused silica, and was suppressed upon addition of MeCN to the BGE, another source of adsorption than pure ion-ion interaction seems plausible. In the bare silica capillary the mobility, mu, of the analytes followed roughly the pH dependence of a monoacidic base, but two deviations from the sigmoid theoretical curve were evident: (i) even at low pH the mobilities were not constant; they decreased in contrary with pH over the entire range; (ii) the apparent pK(a) values of two analytes, derived at the pH with halve the mobility at low pH, are significantly smaller than the thermodynamic pK(a). Upon modifying the expression for mu = f(pH), and considering the pH dependence of the negative charge density at the wall by an additional term which takes chromatographic retention into account, an equation was derived which enables the description of the observed electromigration of the analytes as function of pH, pK(a) of analytes and surface silanol groups, actual mobility of analytes, distribution coefficient (or retention factor) due to adsorption including its pH dependence. The interplay of electrophoretic movement and residual adsorptive retention allowed to resolve the analytes finally in an uncoated capillary, namely at pH 7.65 (30 mM ionic strength), whereas at the cost of the robustness of the separation system.


Subject(s)
Antidepressive Agents, Tricyclic/chemistry , Antidepressive Agents, Tricyclic/isolation & purification , Clomipramine/chemistry , Clomipramine/isolation & purification , Electrophoresis, Capillary/methods , Hexadimethrine Bromide/chemistry , Adsorption/drug effects , Algorithms , Buffers , Cations , Chemistry Techniques, Analytical/methods , Clomipramine/analogs & derivatives , Electrophoresis, Capillary/instrumentation , Hexadimethrine Bromide/metabolism , Hydrogen-Ion Concentration , Sensitivity and Specificity , Silicon Dioxide/chemistry , Spectrophotometry, Ultraviolet
19.
Pharmazie ; 57(6): 405-8, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12116878

ABSTRACT

The isolation and identification of the photodegradation products of clomipramine (CIP) in phosphate buffered saline (PBS pH 7.4 and 6.0) solution and methanol under aerobic conditions were studied. Six compounds were identified and four of them were isolated and characterized by spectroscopic methods. A radical mechanism with the participation of the solvent is proposed for the photodegradation of CIP which undergoes homolytic cleavage of the carbon-chlorine bond and also photooxidation of the amine group. CIP was able to induce photohemolysis when it was irradiated in PBS pH 7.4 and in PBS pH 6.0 containing a suspension of human red blood cells (RBCs). The photohemolysis experiments in the presence of additives DABCO and GSH showed nearly total inhibition of drug-induced photohemolysis. The efficient inhibition of photohemolysis by the radical scavenger GSH compared with the inhibition show by DABCO suggests a moderate effect by singlet oxygen. Clomipramine-N-oxide was the unique photoproduct able to induce hemolysis and photohemolysis when it was incubated and irradiated with RBCs for 1 h. A mechanism involving singlet oxygen, radicals and photoproducts is suggested for the reported phototoxicity.


Subject(s)
Antidepressive Agents, Tricyclic/chemistry , Clomipramine/chemistry , Dermatitis, Phototoxic/blood , Erythrocytes/drug effects , Aerobiosis , Antidepressive Agents, Tricyclic/radiation effects , Clomipramine/radiation effects , Hemolysis/drug effects , Hemolysis/radiation effects , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Photochemistry , Photolysis , Ultraviolet Rays
20.
Eur J Med Chem ; 36(6): 539-43, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11525844

ABSTRACT

Ten new 3,5-diphenyl-2-pyrazoline derivatives were synthesised by reacting 1,3-diphenyl-2-propen-1-one with hydrazine hydrate. The chemical structures of the compounds were proved by means of their IR, 1H-NMR spectroscopic data and microanalyses. The antidepressant activities of these compounds were evaluated by the 'Porsolt Behavioural Despair Test' on Swiss-Webster mice. 3-(4-Methoxyphenyl)-5-(3,4-dimethoxyphenyl)-2-pyrazoline, 3-(4-methoxyphenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline and 3-(4-chlorophenyl)-5-(2-chloro-3,4-dimethoxyphenyl)-2-pyrazoline reduced 41.94-48.62% immobility times at 100 mgkg(-1) dose level. In addition, it was found that 4-methoxy and 4-chloro substituents on the phenyl ring at position 3 of the pyrazoline ring increased the antidepressant activity; the replacement of these groups by bromo and methyl substituents decreased activity in mice.


Subject(s)
Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Clomipramine/chemical synthesis , Clomipramine/chemistry , Clomipramine/pharmacology , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Magnetic Resonance Spectroscopy , Male , Mice , Neuropsychological Tests , Pyrazoles/chemistry , Spectrophotometry, Infrared , Structure-Activity Relationship , Swimming , Tranylcypromine/chemical synthesis , Tranylcypromine/chemistry , Tranylcypromine/pharmacology
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