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1.
Sensors (Basel) ; 23(5)2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36904585

RESUMO

Data processing in robotics is currently challenged by the effective building of multimodal and common representations. Tremendous volumes of raw data are available and their smart management is the core concept of multimodal learning in a new paradigm for data fusion. Although several techniques for building multimodal representations have been proven successful, they have not yet been analyzed and compared in a given production setting. This paper explored three of the most common techniques, (1) the late fusion, (2) the early fusion, and (3) the sketch, and compared them in classification tasks. Our paper explored different types of data (modalities) that could be gathered by sensors serving a wide range of sensor applications. Our experiments were conducted on Amazon Reviews, MovieLens25M, and Movie-Lens1M datasets. Their outcomes allowed us to confirm that the choice of fusion technique for building multimodal representation is crucial to obtain the highest possible model performance resulting from the proper modality combination. Consequently, we designed criteria for choosing this optimal data fusion technique.

2.
Bioorg Med Chem Lett ; 49: 128318, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34391892

RESUMO

Lipophilicity is one of the principal QSAR parameters which influences among others the pharmacodynamics and pharmacokinetic properties of a drug candidates. In this paper, the lipophilicity of 14 amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 channel antagonists and phosphodiesterase 4/7 inhibitors with analgesic activity were investigated, using reversed-phase thin-layer chromatography method. It was observed that the retention behavior of the analyzed compounds was dependent on their structural features i.e. an aliphatic linker length, a kind of substituent at 8 position of purine-2,6-dione scaffold as well as on a substitution in a phenyl group. The experimental parameters (RM0) were compared with computationally calculated partition coefficient values by Principal Component Analysis (PCA). To verify the influence of lipophilic parameter of the investigated compounds on their biological activity the Kruskal-Wallis test was performed. The lowest lipophilicity was observed for the compounds with weak PDE4/7 inhibitory potency. The differences between the lipophilicity of potent inhibitors and inactive compounds were statistically significant. It was found that the presence of more lipophilic propoxy- or butoxy- substituents as well as the elongation of the aliphatic chain to propylene one between the purine-2,6-dione core and amide group were preferable for desired multifunctional activity.


Assuntos
Analgésicos/química , Benzenoacetamidas/química , Inibidores da Fosfodiesterase 4/química , Canal de Cátion TRPA1/antagonistas & inibidores , Xantinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Fenilbutiratos/química , Análise de Componente Principal , Relação Quantitativa Estrutura-Atividade
3.
Bioorg Chem ; 115: 105218, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34365058

RESUMO

The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.


Assuntos
Neuralgia/tratamento farmacológico , Pirróis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Pirróis/química , Pirróis/metabolismo , Ratos , Ratos Wistar , Antagonistas da Serotonina/química , Antagonistas da Serotonina/metabolismo , Relação Estrutura-Atividade
4.
Molecules ; 25(17)2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32854402

RESUMO

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.


Assuntos
Antipsicóticos , Simulação de Acoplamento Molecular , Diester Fosfórico Hidrolases/química , Receptor 5-HT1A de Serotonina/química , Receptores de Serotonina/química , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Células Hep G2 , Humanos , Camundongos , Diester Fosfórico Hidrolases/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade
5.
Bioorg Med Chem ; 27(18): 4163-4173, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31383628

RESUMO

On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT1A and 5-HT7 receptors (Ki = 0.2-1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A and 5-HT7 receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Receptores de Serotonina/metabolismo , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Humanos , Relação Estrutura-Atividade
6.
Electrophoresis ; 39(19): 2446-2453, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30051931

RESUMO

Discovering hit compounds and optimization processes in medicinal chemistry nowadays could be improved by predictive tools, based on the relationship between structure of molecules and lipophilic properties. Lipophilicity of drug candidate can affect both the pharmacokinetic and pharmacodynamics properties, in particular, the ability of a molecule to cross the cell membrane. Among the new methods for determination of the lipophilicity of compounds, micellar electrokinetic chromatography (MEKC) is considered to be an appropriate one for bioactive molecules, as it closely mimics the physiological conditions. In this paper MEKC was used for the estimation of the lipophilicity of 24 derivatives of 8-alkoxy-7H-purine-2,6-dione, designed and synthesized as potential antidepressant/anxiolytic and antipsychotic agents. The results of experimental method were compared with calculated in silico parameters (AlogPs and milogP by Virtual Computational Laboratory website, log PPallas by Pallas 3.1, Mlog P by Marvin, log PChemS by ChemSketch, log PChemDraw by ChemBioUltra) using Principal Component Analysis (PCA) method. Finally, using estimated log P values for selected compounds ligand - lipophilicity efficiency (LLE), per cent efficiency index (PEI), and binding efficiency index (BEI) parameters were calculated. Applied MEKC procedure could be used for selection of potential lead structure in a group of 7H-purine-2,6-dione derivatives.


Assuntos
Cromatografia Capilar Eletrocinética Micelar/métodos , Psicotrópicos/química , Xantinas/química , Descoberta de Drogas , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Modelos Lineares , Psicotrópicos/análise , Psicotrópicos/farmacocinética , Xantinas/análise , Xantinas/farmacocinética
7.
J Enzyme Inhib Med Chem ; 33(1): 536-545, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29482394

RESUMO

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9 µM and 20.5 µM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.


Assuntos
Isoquinolinas/farmacologia , Piperazinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Receptores Adrenérgicos alfa 2/metabolismo , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/química , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Testes de Função Plaquetária , Relação Estrutura-Atividade
8.
Bioorg Med Chem ; 25(14): 3638-3648, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28529043

RESUMO

A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED=0.625mg/kg, i.p.).


Assuntos
Antidepressivos/química , Antipsicóticos/química , Piperazinas/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Sulfonamidas/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Sítios de Ligação , Maleato de Dizocilpina/farmacologia , Halogênios/química , Concentração Inibidora 50 , Ligantes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Atividade Motora/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Estrutura Terciária de Proteína , Receptor 5-HT1A de Serotonina/química , Receptores de Dopamina D2/química , Receptores de Serotonina/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia
9.
J Enzyme Inhib Med Chem ; 31(sup3): 10-24, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27353547

RESUMO

A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized and evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT1A, 5-HT7 and mixed 5-HT1A/5-HT7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Imidazóis/farmacologia , Atividade Motora/efeitos dos fármacos , Purinonas/farmacologia , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Antidepressivos/síntese química , Antidepressivos/química , Cromatografia Capilar Eletrocinética Micelar , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Diester Fosfórico Hidrolases/metabolismo , Purinonas/síntese química , Purinonas/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Relação Estrutura-Atividade , Natação
10.
Arch Pharm (Weinheim) ; 349(10): 774-784, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27510801

RESUMO

In our previous papers, we have reported that some 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic, partial agonistic, or antagonistic activity for serotonin 5-HT1A and dopamine D2 receptors. In order to examine further the influence of the substituent in the position 8 of the purine moiety and the influence of the xanthine core on the affinity for serotonin 5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 , and dopamine D2 receptors, two series of 1-arylpiperazynylalkyl derivatives of 8-amino-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for the serotonin 5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 , and dopamine D2 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, the functional assays for the 5-HT1A and D2 receptors were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for 5-HT1A receptors and agonistic, partial agonistic, or antagonistic activity for D2 receptors. In total, 26 new compounds were synthesized, 20 of which were tested in in vitro binding experiments and 5 were tested in in vitro functional assays.


Assuntos
Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Purinas/química , Purinas/farmacologia , Receptores de Dopamina D2/agonistas , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Adenilil Ciclases/metabolismo , Animais , Ligação Competitiva , Cálcio/metabolismo , Células Cultivadas , Antagonistas dos Receptores de Dopamina D2/síntese química , Relação Dose-Resposta a Droga , Humanos , Ensaio Radioligante , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Relação Estrutura-Atividade
11.
Arch Pharm (Weinheim) ; 349(12): 889-903, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27869315

RESUMO

In the search for potential psychotropic agents, a new series of 3,7-dimethyl- and 1,3-dimethyl-8-alkoxypurine-2,6-dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5-16 and 21-32) were synthesized and evaluated for 5-HT1A /5-HT7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-3,7-dimethyl-8-propoxypurine-2,6-dione (16) and 7-(2-hydroxyphenyl)piperazinylalkyl-1,3-dimethyl-8-ethoxypurine-2,6-diones (31 and 32) as potent dual 5-HT1A /5-HT7 receptor ligands with antagonistic activity produced an antidepressant-like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10-5 M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5-HT1 and 5-HT7 receptors, especially in the case of compounds 15 and 16. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.


Assuntos
Antidepressivos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Antidepressivos/síntese química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Isoenzimas/antagonistas & inibidores , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Masculino , Camundongos , Modelos Moleculares , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Agonistas do Receptor de Serotonina/síntese química , Relação Estrutura-Atividade , Teobromina/farmacologia , Teofilina/farmacologia
12.
Acta Pol Pharm ; 73(2): 369-77, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27180429

RESUMO

A series of octahydro- and 6,7-dimethoxy-3,4-dihydro- isoquinolin-2(1H)-yl-alkyl derivatives of imidazo- and pyrimidino[2,1-f]purines were synthesized and biologically evaluated in in vitro competition binding experiments for serotonin 5-HT(1A), 5-HT(6), 5-HT(7), and dopamine D2 receptors and inhibitory potencies for phosphodiesterases - PDE4B1 and PDE10A. The structure-activity relationships allowed to determine the structural features responsible for receptor and enzyme activity. Compound 5 (8-(4-(6,7-dimethoxy-3,4-dihydroiso- quinolin-2(1H)butyl)1,3-dimethyl-H-imidazo[2,1-f]purine-2,4(3H,8H)-dione) could be regarded as promising structure for further modification and detailed mechanistic study for obtained hybrid ligands.


Assuntos
Imidazóis/metabolismo , Inibidores da Fosfodiesterase 4/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Pirimidinonas/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Ligação Competitiva , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/farmacologia , Ligantes , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Diester Fosfórico Hidrolases/química , Ligação Proteica , Pirimidinonas/química , Pirimidinonas/farmacologia , Ensaio Radioligante , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/genética , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/genética , Relação Estrutura-Atividade , Transfecção
13.
Bioorg Med Chem ; 23(13): 3436-47, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25936259

RESUMO

A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic α1 and α2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Hidantoínas/farmacologia , Imidazolidinas/farmacologia , Piperazinas/farmacologia , Animais , Ansiolíticos/síntese química , Antidepressivos/síntese química , Antipsicóticos/síntese química , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Aripiprazol/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Dextroanfetamina , Hidantoínas/síntese química , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Hipercinese/fisiopatologia , Imidazolidinas/síntese química , Masculino , Camundongos , Piperazinas/síntese química , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Relação Estrutura-Atividade , Natação
14.
Arch Pharm (Weinheim) ; 348(4): 229-41, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25773578

RESUMO

In our previous paper, we have reported that some 8-alkoxy-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic activity for the serotonin 5-HT1A receptor. In order to examine the influence of the substituent in the position 8 of the purine moiety on the affinity for the serotonin 5-HT1A , 5-HT2A , and 5-HT7 receptors, a series of 7-arylpiperazynylalkyl and 7-tetrahydroisoquinolinylalkyl (THIQ) derivatives of 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for serotonin 5-HT1A , 5-HT2A , and 5-HT7 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, functional assays for the 5-HT1A receptor were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for this receptor.


Assuntos
Purinas/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Animais , Ligação Competitiva , Desenho de Fármacos , Ligantes , Estrutura Molecular , Ligação Proteica , Purinas/síntese química , Purinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Relação Estrutura-Atividade
15.
Arch Pharm (Weinheim) ; 348(4): 242-53, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25773907

RESUMO

To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 ) and dopamine (D2 ) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A /5-HT7 /D2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Purinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/metabolismo , Antipsicóticos/síntese química , Antipsicóticos/metabolismo , Comportamento Animal/efeitos dos fármacos , Biotransformação , Antagonistas dos Receptores de Dopamina D2/síntese química , Antagonistas dos Receptores de Dopamina D2/metabolismo , Desenho de Fármacos , Ligantes , Fígado/metabolismo , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Purinas/síntese química , Purinas/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Relação Estrutura-Atividade , Natação
16.
Heart Lung Circ ; 24(8): 817-23, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25797323

RESUMO

BACKGROUND: Although both chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) are characterised by chronic, systemic inflammation, their reciprocal interactions are poorly understood. The purpose of this study was to determine the concentrations of both inflammatory and oxidative stress biomarkers in the serum and exhaled breath condensate (EBC) of COPD patients, either with coexisting CVD or without cardio-vascular comorbidities. METHODS: Twenty-four COPD patients with CVD were allocated to group A, 20 COPD patients without CVD were assigned to group B and 16 healthy patients were included as a control. A medical history and physical examination were performed, and the following were measured: serum CRP concentration, glucose level, uraemic acid level and lipid profile. In addition 8-isoprostane, LTB4 and IL-8 concentrations were measured both in serum and EBC. Spirometry, six-minute walk test and echocardiography were performed in all subjects. RESULTS: EBC concentrations of 8-isoprostane and LTB4, and serum levels of CRP, 8-soprostane, LTB4, IL-8 were significantly higher in COPD patients than in healthy controls. COPD patients with CVD were not found to have higher concentrations of the assessed markers than those without CVD, neither in the serum nor EBC. CRP, 8-isoprostane and LTB4 levels in serum, and IL-8 concentration in EBC correlated negatively with the value of forced expiratory volume in one second. CONCLUSIONS: Although systemic inflammation coexists with COPD, it is not elevated in COPD patients with CVD. Since this phenomenon may result from treatment with statins, future studies should state whether COPD patients could benefit from the additional statin therapy.


Assuntos
Doenças Cardiovasculares/metabolismo , Dinoprosta/análogos & derivados , Mediadores da Inflamação/metabolismo , Interleucina-8/metabolismo , Leucotrieno B4/metabolismo , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Biomarcadores/metabolismo , Testes Respiratórios , Doenças Cardiovasculares/epidemiologia , Comorbidade , Dinoprosta/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia
17.
Acta Pol Pharm ; 72(4): 663-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26647622

RESUMO

The present study is a part of our physicochemical and pharmacological studies in a group of tricyclic theophylline derivatives. The investigated compounds exhibit different pharmacological profiles in comparison to theophylline and have been tested as potential antidepressant and/or antipsychotic agents. The differences in pharmacological action between theophylline and their tricyclic derivatives can be explained by their various physicochemical properties, especially lipophilicity. The chromatographic behavior of twenty three derivatives of imidazo[2,1-ƒ]theophylline was investigated, using reversed-phase high performance liquid chromatography (RP-HPLC) method. Moreover, partition coefficients and selected pharmacokinetic parameters were calculated computationally. Principal component analysis (PCA) method was used to establish the relationship between obtained experimental and computational parameters.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Imidazóis/química , Teofilina/análogos & derivados , Análise de Componente Principal , Solubilidade , Teofilina/química
18.
Acta Pol Pharm ; 71(3): 379-83, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25265816

RESUMO

The chromatographic parameters of arylpiperazinylpropyl derivatives of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione were investigated using reversed-phase thin layer chromatography method. The results revealed that R(M0) of investigated compounds depended on substituent in arylpiperazinyl fragment as well as on a nature of (cycloalkyl)aromatic ring at 5 position of imidazolidine-2,4-dione and at 7 position of imidazo[2,1-f]theophylline. The R(M0) parameters were compared with computationally calculated partition coefficients values by principal component analysis (PCA). To verify the influence of lipophilic parameter of investigated compounds on their biological activity the statistical analysis of Mann-Whitney was performed.


Assuntos
Cromatografia de Fase Reversa/métodos , Cromatografia em Camada Fina/métodos , Hidantoínas/análise , Piperazinas/análise , Purinas/análise , Simulação por Computador , Estrutura Molecular , Análise de Componente Principal
19.
J Chem Inf Model ; 53(3): 638-48, 2013 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-23398329

RESUMO

Recent breakthroughs in crystallographic studies of G protein-coupled receptors (GPCRs), together with continuous progress in molecular modeling methods, have opened new perspectives for structure-based drug discovery. A crucial enhancement in this area was development of induced fit docking procedures that allow optimization of binding pocket conformation guided by the features of its active ligands. In the course of our research program aimed at discovery of novel antipsychotic agents, our attention focused on dopaminergic D2 and D1 receptors (D2R and D1R). Thus, we decided to investigate whether the availability of a novel structure of the closely related D3 receptor and application of induced fit docking procedures for binding pocket refinement would permit the building of models of D2R and D1R that facilitate a successful virtual screening (VS). Here, we provide an in-depth description of the modeling procedure and the discussion of the results of a VS benchmark we performed to compare efficiency of the ligand-optimized receptors in comparison with the regular homology models. We observed that application of the ligand-optimized models significantly improved the VS performance both in terms of BEDROC (0.325 vs 0.182 for D1R and 0.383 vs 0.301 for D2R) as well as EF1% (20 vs 11 for D1R and 18 vs 10 for D2R). In contrast, no improvement was observed for the performance of a D2R model built on the D3R template, when compared with that derived from the structure of the previously published and more evolutionary distant ß2 adrenergic receptor. The comparison of results for receptors built according to various protocols and templates revealed that the most significant factor for the receptor performance was a proper selection of "tool ligand" used in induced fit docking procedure. Taken together, our results suggest that the described homology modeling procedure could be a viable tool for structure-based GPCR ligand design, even for the targets for which only a relatively distant structural template is available.


Assuntos
Receptores de Dopamina D1/química , Receptores de Dopamina D2/química , Sítios de Ligação , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Padrões de Referência , Homologia Estrutural de Proteína , Interface Usuário-Computador
20.
Arch Pharm (Weinheim) ; 346(11): 832-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24123186

RESUMO

The multireceptor strategy was implemented to obtain potential antipsychotics and/or antidepressants in a series of long-chain arylpiperazines bearing a tricyclic theophylline fragment. Their binding profile toward monoaminergic receptors (α1, 5-HT(1A), 5-HT(2A), 5-HT6, 5-HT7, D2, D3) was determined as well. The selected compounds 7 and 9 were tested in functional in vivo models and showed, like atypical antipsychotic drugs, presynaptic 5-HT(1A) receptor agonistic and postsynaptic 5-HT(1A), 5-HT(2A), and D2 receptor antagonistic activity.


Assuntos
Antidepressivos Tricíclicos/síntese química , Antidepressivos Tricíclicos/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Teofilina/síntese química , Teofilina/farmacologia , Animais , Antidepressivos Tricíclicos/metabolismo , Antipsicóticos/metabolismo , Comportamento Animal/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/síntese química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ratos Wistar , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade , Teofilina/análogos & derivados , Teofilina/metabolismo
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