Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 866
Filtrar
1.
J Photochem Photobiol B ; 202: 111686, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731078

RESUMO

In this work, a molecular hydrogel made of gelator (S)-4-((3-methyl-1-(nonylamino)-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SVN) has been employed as soft container to modify the photochemical and photophysical behavior of the antipsychotic drug cyamemazine (CMZ). The interaction of CMZ with the gel network has been evidenced by fluorescence spectroscopy through a hypsochromic shift of the emission band (from λmax = 521 nm in solution to λmax = 511 nm in the gel) and an increase of the fluorescence lifetime (5.6 ns in PBS vs. 7.2 ns in the gel). In the laser flash photolysis experiments on CMZ/SVN systems, the CMZ triplet excited state (3CMZ*), monitored at λ = 320 nm, has been more efficiently generated and became much longer-lived than in solution (2.7 µs vs. 0.7 µs); besides, photochemical ionization leading to the radical cation CMZ+• was disfavored. In the steady-state experiments, photooxidation of CMZ to afford the N,S-dioxide derivative CMZ-SONO has been retarded in the gel, which provides a more lipophilic and constrained microenvironment. Both the photophysical properties and the photoreactivity are in agreement with CMZ located in a less polar domain when entrapped in the supramolecular gel, as result of the interaction of the drug with the fibers of the supramolecular SVN gel.


Assuntos
Antipsicóticos/química , Hidrogéis/química , Fenotiazinas/química , Lasers , Oxirredução , Fotólise/efeitos da radiação , Espectrometria de Fluorescência
2.
Eur J Med Chem ; 185: 111857, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734022

RESUMO

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Triptaminas/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Humanos , Ligantes , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/química , Células Tumorais Cultivadas
3.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540025

RESUMO

In order to search for novel antipsychotics acting through the D2 receptor, it is necessary to know the structure-activity relationships for dopamine D2 receptor antagonists. In this context, we constructed the universal three-dimensional quantitative structure-activity relationship (3D- QSAR) model for competitive dopamine D2 receptor antagonists. We took 176 compounds from chemically different groups characterized by the half maximal inhibitory concentration (IC50)from the CHEMBL database and docked them to the X-ray structure of the human D2 receptor in the inactive state. Selected docking poses were applied for Comparative Molecular Field Analysis (CoMFA) alignment. The obtained CoMFA model is characterized by a cross-validated coefficient Q2 of 0.76 with an optimal component of 5, R2 of 0.92, and an F value of 338.9. The steric and electrostatic field contributions are 67.4% and 32.6%, respectively. The statistics obtained prove that the CoMFA model is significant. Next, the IC50 of the 16 compounds from the test set was predicted with R2 of 0.95. Finally, a progressive scrambling test was carried out for additional validation. The CoMFA fields were mapped onto the dopamine D2 receptor binding site, which enabled a discussion of the structure-activity relationship based on ligand-receptor interactions. In particular, it was found that one of the desired steric interactions covers the area of a putative common allosteric pocket suggested for some other G protein-coupled receptors (GPCRs), which would suggest that some of the known dopamine receptor antagonists are bitopic in their essence. The CoMFA model can be applied to predict the potential activity of novel dopamine D2 receptor antagonists.


Assuntos
Antipsicóticos/química , Antagonistas dos Receptores de Dopamina D2/química , Receptores de Dopamina D2/química , Sítios de Ligação/efeitos dos fármacos , Dopamina/química , Dopamina/farmacologia , Composição de Medicamentos , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Software , Eletricidade Estática
4.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416290

RESUMO

Neuroleptics and antiepileptics are excreted in saliva, which can, therefore, be very useful in determining their concentration in the body. This study presents a method developed to simultaneously identify five neuroleptics-olanzapine, quetiapine, risperidone, aripiprazole, and clozapine-and the antiepileptic carbamazepine together with their metabolites: N-demethyl olanzapine, norquetiapine, 9-OH-risperidone, dehydroaripiprazole, N-desmethylclozapine, and carbamazepine-10,11 epoxide. Chlordiazepoxide was used as the internal standard. Strata-X-C columns were used for isolation of the compounds. Chromatographic analysis was carried out using UHPLC with a diode array detector (DAD). A mixture of acetonitrile and water with the addition of formic acid and 0.1% triethylamine was used as the mobile phase. The developed method was validated by determining the linearity for all analytes in the range 10-1000 ng/mL and the value of R2 > 0.99. Intra- and inter-day precision were also determined, and the relative standard deviation (RSD) value in both cases did not exceed 15%. To determine the usefulness of the developed method, saliva samples were collected from 40 people of both sexes treated with the tested active substances both in monotherapy and in polypragmasy. In all cases, the active substances tested were identified.


Assuntos
Anticonvulsivantes/farmacologia , Antipsicóticos/farmacocinética , Cromatografia Líquida de Alta Pressão , Saliva/metabolismo , Anticonvulsivantes/química , Antipsicóticos/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Reprodutibilidade dos Testes
5.
Ultrason Sonochem ; 59: 104696, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31430655

RESUMO

We report a novel electrochemical sensor for the sensitive and selective determination of the antipsychotic drug chlorpromazine (CPZ) based on the iron (Fe) nanoparticles-loaded graphene oxide (GO-Fe)/three dimensional (3D) honeycomb-like zinc oxide (ZnO) nanohybrid modified screen printed carbon electrode (SPCE). The 3D hierarchical honeycomb-like ZnO was synthesized using a novel aqueous hydrothermal method and the GO-Fe/ZnO nanohybrid was prepared based on an inexpensive and fast sonochemical method using a high-intensity ultrasonic bath (Delta DC200H, 200 W, 40 KHz). Characterizations including scanning electron microscopy, elemental mapping, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy were carried out as part of this work. The electrocatalytic oxidation behavior of CPZ at various electrodes was investigated using the cyclic voltammetry technique, through which the GO-Fe/ZnO modified SPCE was identified as the best performing electrode. The quantitative determination of CPZ was then performed using the differential pulse voltammetry technique. The as-prepared GO-Fe/ZnO/SPCE sensor exhibited a quick and sensitive response towards the oxidation of CPZ with linear concentration ranges from 0.02 to 172.74 µM and 222.48 to 1047.74 µM. The modified SPCE sensor displayed a low detection limit (LOD) of 0.02 µM and a high sensitivity of 7.56 µA µM-1 cm-2. The proposed sensor also showed remarkable operational and storage stability, reproducibility, and repeatability. Furthermore, the practicability of the GO-Fe/ZnO/SPCE sensor has been verified with real sample analysis using commercial antipsychotic CPZ tablets and human urine samples, and adequate recovery has been achieved.


Assuntos
Clorpromazina/análise , Grafite/química , Ferro/química , Limite de Detecção , Nanotecnologia , Ondas Ultrassônicas , Óxido de Zinco/química , Antipsicóticos/análise , Antipsicóticos/química , Antipsicóticos/urina , Técnicas de Química Sintética , Clorpromazina/química , Clorpromazina/urina , Eletroquímica , Eletrodos , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas Metálicas/química , Modelos Moleculares , Conformação Molecular
6.
Phys Chem Chem Phys ; 21(28): 15463-15470, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31257373

RESUMO

Effective treatment of disorders of the central nervous system can often be achieved using bioactive molecules of similar moieties to those known to be tolerable. A better understanding of the solid-state characteristics of such molecules could thereby create new opportunities for research on pharmaceutical preparations and drug prescriptions, while information about their rich intramolecular dynamics may well add an important aspect in the field of in silico drug discovery. We have therefore investigated three different antipsychotic drugs: haloperidol (C21H23ClFNO2, HAL), aripiprazole (C23H27Cl2N3O2, APZ) and quetiapine hemifumarate (C21H25N3O2S·0.5C4H4O4, QTP) based on similarities either in their structures, hydrophobic and hydrophilic moieties, or in their modes of action, typical or atypical. Our aim was to test the structural and molecular stability of these three different antipsychotics. To this end, we compared the molecular vibrations observed by inelastic neutron spectroscopy of these systems with those from theoretical periodic calculations of the crystalline antipsychotics using the Vienna ab initio simulation package (VASP). While most of the observed features in the lattice region were reasonably well represented by the calculations, the overall spectra were relatively complex, and hence traditional assignment procedures for the approximately 600 normal modes in the unit cell were not possible. These results indicate that in the search for new drug candidates, not only analysis of the flexibility of the receptor, but also the dynamics of the active molecules play a role in improving the prediction of binding affinities.


Assuntos
Antipsicóticos/química , Conformação Molecular , Ligações de Hidrogênio
7.
Curr Med Chem ; 26(25): 4885-4913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291870

RESUMO

Schizophrenia is a chronic psychiatric disorder that affects about 1 in 100 people around the world and results in persistent emotional and cognitive impairments. Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Descoberta de Drogas , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Humanos , Estrutura Molecular
8.
ACS Chem Biol ; 14(8): 1780-1792, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31339684

RESUMO

Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments, and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2, and 7 determines the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism for fine-tuning the intrinsic efficacy of D2R agonists.


Assuntos
Antipsicóticos/metabolismo , Aripiprazol/metabolismo , Agonistas de Dopamina/metabolismo , Receptores de Dopamina D2/metabolismo , Antipsicóticos/química , Aripiprazol/química , Sítios de Ligação , Dopamina/química , Dopamina/metabolismo , Agonistas de Dopamina/química , Indóis/química , Indóis/metabolismo , Ligantes , Conformação Molecular , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Receptores de Dopamina D2/química , Receptores de Dopamina D2/genética
9.
Eur J Med Chem ; 180: 673-689, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31357129

RESUMO

Schizophrenia is a complex disease with not fully understood pathomechanism, involving many neurotransmitters and their receptors. This is why it is best treated with multi-target drugs, such as second generation antipsychotics. Here we present 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles (1-20) which are ligands of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptors and display affinity in the nanomolar range. These compounds were designed as modifications of the virtual hit experimentally confirmed, D2AAK1, and synthesized from indole or 5-alkoxyindoles and N-substituted piperidin-4-ones in methanol in the presence of potassium hydroxide. Compound 9 was subjected to X-ray studies and it crystallizes in the centrosymmetric monoclinic space group P21/c with one molecule in an asymmetric unit. Three most potent compounds (5, 9 and 17) turned out to be antagonists of both D2 and 5-HT2A receptors what is beneficial for their potential application as antipsychotics. Compound 5 was subjected to behavioral studies and exhibited antipsychotic, pro-cognitive and antidepressant activity in appropriate mice models. Structure-activity relationships for compounds 1-20 were rationalized using molecular docking. It was found that, in general, bulky C5-alkoxy substituents at the indole moiety are not favorable as they direct towards aqueous environment of the extracellular vestibule. Keywords: antipsychotics; behavioral studies, G protein-coupled receptors; indole derivatives; multi-target compounds; schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Indóis/farmacologia , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Migração Animal/efeitos dos fármacos , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Células CHO , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Ligantes , Masculino , Camundongos , Estrutura Molecular , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
10.
Int J Pharm Compd ; 23(2): 113-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085776

RESUMO

Schizophrenia is a serious, disabling, enduring, and relapsing mental illness which causes problems with the ability to think, feel, and perceive things clearly. One cause of relapse and readmission to a hospital is poor compliance with antipsychotic medication, often due to its adverse effects. Schizophrenia may also affect a person's insight, interfering with their ability to appreciate the benefit of taking medication long term. The relapse rate is significantly higher in those who have discontinued antipsychotic medication. Penfluridol is an unusual, potent, long-acting, first-generation, oral antipsychotic agent indicated for the treatment of chronic schizophrenia, acute psychosis, and Tourette syndrome. It may be considered a depot medication, as it is administered once a week. Despite this positive analysis, and the unique added value of this medication to psychotic, non-compliant patients, Janssen-Cilag, the sole manufacturer of penfluridol worldwide, decided to stop production in 2009. This decision forced many psychotic patients worldwide to abandon the once-a-week convenient treatment and to replace it with a daily, oral treatment or a depot injection. Because penfluridol is no longer commercially available, it has created an opportunity for compounding pharmacists worldwide to accept this challenge and offer this medication to psychiatrists because of its clinical therapeutics. For the past 5 years, penfluridol has been available to compounding pharmacists in Israel and has received favorable feedback from physicians and patients.


Assuntos
Antipsicóticos/farmacologia , Penfluridol , Esquizofrenia , Administração Oral , Antipsicóticos/química , Humanos , Injeções , Penfluridol/farmacologia
11.
Anal Sci ; 35(7): 815-819, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30956261

RESUMO

This study attempted to determine the phenothiazine antipsychotics concentration in serum and whole blood samples using various diatomaceous earth-based solid-phase columns and elution solvents and subsequently evaluate their efficiency. Phenothiazine antipsychotics concentrations of 5 - 2000 ng/mL were extracted from serum and whole blood using each column. All compounds were analyzed using liquid chromatography-tandem mass spectrometry. Phenothiazine antipsychotics extraction in serum and whole blood using diatomaceous earth-based solid-phase columns seemed to have an affinity with the elution solvent.


Assuntos
Antipsicóticos/sangue , Análise Química do Sangue/métodos , Terra de Diatomáceas/química , Fenotiazinas/sangue , Antipsicóticos/química , Humanos , Fenotiazinas/química , Solventes/química
12.
Molecules ; 24(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013866

RESUMO

Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.


Assuntos
Ansiolíticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Antipsicóticos/uso terapêutico , Canabidiol/uso terapêutico , Cannabis/química , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Ansiolíticos/efeitos adversos , Ansiolíticos/química , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/química , Antipsicóticos/efeitos adversos , Antipsicóticos/química , Canabidiol/efeitos adversos , Canabidiol/química , Ensaios Clínicos como Assunto , Epilepsia/patologia , Epilepsia/fisiopatologia , Humanos , Convulsões/patologia , Convulsões/fisiopatologia
13.
Arch Pharm (Weinheim) ; 352(5): e1800373, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025433

RESUMO

N'-Cyanoisonicotinamidine and N'-cyanopicolinamidine derivatives, linked to an arylpiperazine moiety, were prepared and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated. Several of the newly synthesized compounds, tested by binding studies, showed nanomolar affinity at the 5-HT1A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1 , D2 , α1 , and α2 ). Compound 8e (Ki = 21.4 nM) was the most affine for the 5-HT2C receptor, showing, at the same time, a high selectivity with respect to the other receptors analyzed. Compounds 4a and 4c, instead, showed an interesting mixed 5-HT1A /5-HT2C activity with Ki values of 21.3/11.5 and 23.2/6.48 nM, respectively. The compounds with better affinity and selectivity binding profiles toward 5-HT2C (4a, 4c, 8b, and 8e) were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that compounds 4a, 8b, and 8e exerted antidepressant-like effects and 4a and 8e revealed also significant anxiolytic properties. Among the developed derivatives, the most promising compound seems to be 4a, which displayed antipsychotic-, antidepressant- and anxiolytic-like properties. No side effects, like catalepsy, motor-impairment or ethanol-potentiating effects, were observed after the injection of the tested compounds.


Assuntos
Amidinas/metabolismo , Antipsicóticos/farmacologia , Simulação de Acoplamento Molecular , Receptor 5-HT2C de Serotonina/metabolismo , Amidinas/síntese química , Amidinas/química , Amidinas/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
14.
Artigo em Inglês | MEDLINE | ID: mdl-30870786

RESUMO

Phenothiazine molecules are effective and commonly used antipsychotic drugs, especially in the treatment of schizophrenia. However, they produce strong extrapyramidal side-effects manifested by drug-induced parkinsonism. Because Parkinson's disease as a neurodegenerative illness is associated with the formation of amyloid fibrils in neuronal cells, it is postulated that the development of phenothiazine-induced parkinsonism may be related to the phenothiazine-induced formation of fibrillar aggregates. The effect of phenothiazine compounds (fluphenazine (FPh), chlorpromazine (ChP) and propionylpromazine (PP)) on the fibrillogenesis of poly-l-lysine (PLL) was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA), vibrational circular dichroism (VCD), transmission electron microscopy (TEM) and Congo red binding assay. The fibrillogenesis of PLL is accompanied by fibril formation with charged or uncharged polypeptides with PPII (polyproline-like extended helix), α-helix or ß-sheet conformations. All of the phenothiazine molecules investigated effectively reduced the temperature required to induce the formation of ß-sheet-rich fibrils from α-helix-rich fibrils of PLL.


Assuntos
Amiloide/metabolismo , Antipsicóticos/efeitos adversos , Doença de Parkinson Secundária/etiologia , Fenotiazinas/efeitos adversos , Polilisina/metabolismo , Agregação Patológica de Proteínas/induzido quimicamente , Estrutura Secundária de Proteína/efeitos dos fármacos , Amiloide/química , Amiloide/ultraestrutura , Antipsicóticos/química , Dicroísmo Circular , Humanos , Modelos Moleculares , Doença de Parkinson Secundária/metabolismo , Fenotiazinas/química , Polilisina/química , Agregação Patológica de Proteínas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
15.
Rapid Commun Mass Spectrom ; 33(11): 1024-1035, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30889624

RESUMO

RATIONALE: Brexpiprazole is a novel serotonin-dopamine activity modulator approved by the USFDA in July 2015 for the treatment of schizophrenia and as an adjunctive therapy with other antidepressants for major depressive disorder in adults. However, limited numbers of metabolites are reported in the literature for brexpiprazole. Our prime intent behind this study is to revisit metabolite profiling of brexpiprazole and to identify and characterize all possible in vitro and in vivo metabolites. METHODS: Firstly, the site of metabolism for brexpiprazole was predicted by a Xenosite web predictor model. Secondly, in vitro metabolite profiling was performed by incubating the drug individually with rat liver microsomes, human liver microsomes and rat S9 fraction at 37°C for 1 h in incubator shaker. Finally, for in vivo metabolite identification, a 50 mg kg-1 dose of brexpiprazole was administered to male Sprague-Dawley rats and the presence of various metabolites was confirmed in rat plasma, urine and feces. RESULTS: The predicted atomic site of metabolism was obtained as a color gradient by the Xenosite web predictor tool and, from this study, probable metabolites were listed. In total, 14 phase I and 2 phase II metabolites were identified and characterized in the in vitro and in vivo matrices using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC/QTOF-MS/MS). The majority of metabolites were found in the sample incubated with human liver microsomes and in rat urine, while in the other matrices only a few metabolites were detected. CONCLUSIONS: All the 16 metabolites were identified and characterized using UHPLC/QTOF-MS/MS. The study revealed that brexpiprazole is metabolized via hydroxylation, glucuronidation, S-oxidation, N-oxidation, dioxidation, oxidative deamination, N-dealkylation, etc.


Assuntos
Antipsicóticos/química , Antipsicóticos/metabolismo , Quinolonas/química , Quinolonas/metabolismo , Tiofenos/química , Tiofenos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quinolonas/sangue , Quinolonas/urina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tiofenos/sangue , Tiofenos/urina
16.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901926

RESUMO

Schizophrenia is a chronic mental disease, affecting around 1% of the general population. Schizophrenia is characterized by productive, negative, affective, and disorganization symptoms, and cognitive deficits. Cognitive deficits prevail in most of the schizophrenia patients and are one of the most disabling symptoms. They usually occur before the acute episode of the disease and tend to become chronic with no satisfactory treatment from antipsychotic drugs. Because of their early manifestation in patients' lives, cognitive deficits are suggested to be the primary symptom of schizophrenia. The pathogenesis of cognitive deficits in schizophrenia is not fully understood. They are linked with hypofrontality, which is a decrease in blood flow and glucose metabolism in the prefrontal lobe of schizophrenia-suffering patients. Hypofrontality is linked with disturbances of the corticolimbothalamic circuit, important for cognition and memory in humans. The circuit consists of a group of neuroanatomic structures and hypothetically any disturbance in them may result in cognitive deficits. We present a translational preclinical model of understanding how antipsychotic medication may decrease the N-methyl-D-aspartic acid (NMDA) receptors' activity and produce dysfunctions in the corticolimbothalamic circuit and hypofrontality. From several pharmacological experiments on rats, including mainly our own recent findings, we collected data that suggest that antipsychotic medication may maintain and escalate hypofrontality in schizophrenia, decreasing NMDA receptor activity in the corticolimbothalamic circuit in the human brain. We discuss our findings within the literature of the subject.


Assuntos
Antipsicóticos/química , Córtex Pré-Frontal/irrigação sanguínea , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/química , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/metabolismo , Humanos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
17.
Nat Struct Mol Biol ; 26(2): 121-128, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30723326

RESUMO

Many drugs target the serotonin 2A receptor (5-HT2AR), including second-generation antipsychotics that also target the dopamine D2 receptor (D2R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT2AR in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT2AR is structurally similar to 5-HT2CR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT2AR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT2AR significantly differs around extracellular loops 1 and 2 from that in D2R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT2AR-selective drugs.


Assuntos
Antipsicóticos/química , Antipsicóticos/metabolismo , Dibenzotiepinas/química , Dibenzotiepinas/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Risperidona/química , Risperidona/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Estrutura Secundária de Proteína
18.
ACS Appl Mater Interfaces ; 11(10): 9716-9723, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30775906

RESUMO

We developed floating electrode-based carbon nanotube biosensors for the monitoring of antipsychotic drug effects on the dopamine release from PC12 cells under potassium stimulation. Here, carbon nanotube field-effect transistors with floating electrodes were functionalized with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•) radicals by Nafion films. This method allows us to build selective biosensors for dopamine detection with a detection limit down to 10 nM even in the presence of other neurotransmitters such as glutamate and acetylcholine, resulting from the selective interaction between ABTS• radicals and dopamine. The sensors were also utilized to monitor the real-time release of dopamine from PC12 cells upon the stimulation of high-concentrated potassium solutions. Significantly, the antipsychotic effects of pimozide on the dopamine release from potassium-stimulated PC12 cells could also be evaluated in a concentration-dependent manner by using the sensors. The quantitative and real-time evaluation capability of our strategy should provide a versatile tool for many biomedical studies and applications.


Assuntos
Antipsicóticos/química , Técnicas Biossensoriais , Dopamina/isolamento & purificação , Nanotubos de Carbono/química , Animais , Antipsicóticos/farmacologia , Benzotiazóis/química , Dopamina/química , Dopamina/farmacologia , Liberação Controlada de Fármacos , Polímeros de Fluorcarboneto/química , Radicais Livres/química , Humanos , Transtornos Mentais/tratamento farmacológico , Células PC12 , Potássio/farmacologia , Ratos , Ácidos Sulfônicos/química
19.
Arch Pharm (Weinheim) ; 352(4): e1800306, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30702760

RESUMO

A series of benzamide derivatives possessing potent dopamine D2 , serotonin 5-HT1A , and 5-HT2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5-(4-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy)-N-cyclopropyl-2-fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D2 , 5-HT1A , and 5-HT2A receptors, but was also endowed with low to moderate activities for the 5-HT2C , H1 , and M3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Benzamidas/síntese química , Benzamidas/química , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Fenciclidina/toxicidade , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Esquizofrenia/fisiopatologia , Relação Estrutura-Atividade
20.
AAPS PharmSciTech ; 20(3): 95, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30694404

RESUMO

Haloperidol (Hal) is a well-known typical antipsychotic. Hepatic first pass metabolism leads to its limited oral bioavailability. This study aimed at enhancing transdermal delivery of Hal via spanlastic formulae. Hal-loaded spanlastics of Span®60 and an edge activator (EA) were successfully prepared by ethanol injection method according to a 31.41 full factorial design. In this design, independent variables were X1, EA type, and X2, Span®60 to EA ratio. Y1, percentage entrapment efficiency (EE%); Y2, particle size (PS); Y3, deformability index (DI); and Y4, percentage drug released after 4h (Q4h), were chosen as dependent variables. The Fourier-transform infrared spectral analysis showed no considerable chemical interaction between Hal and the used excipients. Both factors affected significantly all the responses except DI. Desirability of each prepared formula was calculated based on maximizing EE% and Q4h and minimizing PS. Formula F6, with X1, Tween®80, and X2, 8:2, had the highest desirability value followed by F7, with X1, Tween®80, and X2, 6:4, and both were chosen as selected formulae (SF) for further investigation. F6 (having more entrapped Hal), F7 (of smaller PS), and Hal solution in propylene glycol were subjected to ex vivo permeation test through newborn rat skin. Both formulae showed marked enhancement in drug permeation compared with drug solution. The significantly higher Q36h and J36h of F7 from F6 may indicate that the smaller particle size aided more than higher entrapment in achieving a higher permeation for Hal of 3.5±0.2µg/cm2.h. These results are promising for further investigation of this formula.


Assuntos
Antipsicóticos/administração & dosagem , Haloperidol/administração & dosagem , Administração Cutânea , Animais , Animais Recém-Nascidos , Antipsicóticos/química , Antipsicóticos/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/metabolismo , Composição de Medicamentos , Haloperidol/química , Haloperidol/farmacocinética , Tamanho da Partícula , Polissorbatos , Ratos , Pele/metabolismo , Absorção Cutânea
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA