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[PMID]:29304113
[Au] Autor:Shao YM; Ma X; Paira P; Tan A; Herr DR; Lim KL; Ng CH; Venkatesan G; Klotz KN; Federico S; Spalluto G; Cheong SL; Chen YZ; Pastorin G
[Ad] Endereço:Department of Pharmacy, National University of Singapore, Singapore.
[Ti] Título:Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment.
[So] Source:PLoS One;13(1):e0188212, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 µM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 µM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 µM), hepatotoxicity (up to 30 µM) or cardiotoxicity (up to 30 µM).
[Mh] Termos MeSH primário: Antagonistas do Receptor A2 de Adenosina/farmacologia
Antiparkinsonianos/farmacologia
Agonistas de Dopamina/farmacologia
Doença de Parkinson/tratamento farmacológico
Doença de Parkinson/metabolismo
Receptor A2A de Adenosina/metabolismo
Receptores de Dopamina D2/agonistas
Receptores de Dopamina D2/metabolismo
[Mh] Termos MeSH secundário: Antagonistas do Receptor A2 de Adenosina/química
Antagonistas do Receptor A2 de Adenosina/farmacocinética
Inibidores de Adenilil Ciclase/química
Inibidores de Adenilil Ciclase/farmacocinética
Inibidores de Adenilil Ciclase/farmacologia
Animais
Animais Geneticamente Modificados
Antiparkinsonianos/química
Antiparkinsonianos/farmacocinética
Células CHO
Cricetulus
Agonistas de Dopamina/química
Agonistas de Dopamina/farmacocinética
Drosophila/genética
Drosophila/metabolismo
Descoberta de Drogas
Avaliação Pré-Clínica de Medicamentos
Seres Humanos
Transtornos Parkinsonianos/tratamento farmacológico
Transtornos Parkinsonianos/genética
Transtornos Parkinsonianos/metabolismo
Piperazinas/química
Piperazinas/farmacocinética
Piperazinas/farmacologia
Pirimidinas/química
Pirimidinas/farmacocinética
Pirimidinas/farmacologia
Ensaio Radioligante
Máquina de Vetores de Suporte
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adenosine A2 Receptor Antagonists); 0 (Adenylyl Cyclase Inhibitors); 0 (Antiparkinson Agents); 0 (DRD2 protein, human); 0 (Dopamine Agonists); 0 (Piperazines); 0 (Pyrimidines); 0 (Receptor, Adenosine A2A); 0 (Receptors, Dopamine D2)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188212


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Rizzo, Luiz Vicente
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[PMID]:28939444
[Au] Autor:Carvalho de Freitas R; Lonien SCH; Malvezi AD; Silveira GF; Wowk PF; da Silva RV; Yamauchi LM; Yamada-Ogatta SF; Rizzo LV; Bordignon J; Pinge-Filho P
[Ad] Endereço:Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970, Londrina, Paraná, Brazil.
[Ti] Título:Trypanosoma cruzi: Inhibition of infection of human monocytes by aspirin.
[So] Source:Exp Parasitol;182:26-33, 2017 Nov.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell invasion by Trypanosoma cruzi and its intracellular replication are essential for progression of the parasite life cycle and development of Chagas disease. Prostaglandin E2 (PGE ) and other eicosanoids potently modulate host response and contribute to Chagas disease progression. In this study, we evaluated the effect of aspirin (ASA), a non-selective cyclooxygenase (COX) inhibitor on the T. cruzi invasion and its influence on nitric oxide and cytokine production in human monocytes. The pretreatment of monocytes with ASA or SQ 22536 (adenylate-cyclase inhibitor) induced a marked inhibition of T. cruzi infection. On the other hand, the treatment of monocytes with SQ 22536 after ASA restored the invasiveness of T. cruzi. This reestablishment was associated with a decrease in nitric oxide and PGE production, and also an increase of interleukin-10 and interleukin-12 by cells pre-treated with ASA. Altogether, these results reinforce the idea that the cyclooxygenase pathway plays a fundamental role in the process of parasite invasion in an in vitro model of T. cruzi infection.
[Mh] Termos MeSH primário: Adenilil Ciclases/metabolismo
Aspirina/farmacologia
Inibidores de Ciclo-Oxigenase/farmacologia
Monócitos/parasitologia
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adenina/análogos & derivados
Adenina/química
Adenina/farmacologia
Inibidores de Adenilil Ciclase/química
Inibidores de Adenilil Ciclase/farmacologia
Adulto
Animais
Linhagem Celular
Sobrevivência Celular
AMP Cíclico/metabolismo
Citocinas/metabolismo
Dinoprostona/metabolismo
Células Epiteliais/citologia
Células Epiteliais/parasitologia
Seres Humanos
Rim/citologia
Rim/parasitologia
Macaca mulatta
Monócitos/efeitos dos fármacos
Monócitos/metabolismo
Óxido Nítrico/metabolismo
Trypanosoma cruzi/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Cyclooxygenase Inhibitors); 0 (Cytokines); 17318-31-9 (9-(tetrahydro-2-furyl)-adenine); 31C4KY9ESH (Nitric Oxide); E0399OZS9N (Cyclic AMP); EC 4.6.1.1 (Adenylyl Cyclases); JAC85A2161 (Adenine); K7Q1JQR04M (Dinoprostone); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170924
[St] Status:MEDLINE


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[PMID]:28545666
[Au] Autor:Wang Z; Cui Y; Ding G; Zhou M; Ma X; Hou Y; Jiang M; Liu D; Bai G
[Ad] Endereço:State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China.
[Ti] Título:Mahuannin B an adenylate cyclase inhibitor attenuates hyperhidrosis via suppressing ß -adrenoceptor/cAMP signaling pathway.
[So] Source:Phytomedicine;30:18-27, 2017 Jul 01.
[Is] ISSN:1618-095X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Based on the traditional application of traditional Chinese Medicines (TCMs), Ephedra Herba (EH) is used to cure cold fever by inducing sweating, whereas Ephedra Radix (ER) is used to treat hyperhidrosis. Although they come from the same plant, Ephedra sinica Stapf, but have play opposing roles in clinical applications. EH is known to contain ephedrine alkaloids, which is the driver of the physiological changes in sweating, heart rate and blood pressure. However, the active pharmacological ingredients (APIs) of ER and the mechanisms by which it restricts sweating remain unknown. PURPOSE: The current work aims to discover the hidroschesis APIs from ER, as well as to establish its action mechanism. METHODS: UPLC-Q/TOF-MS, PCA, and heat map were utilized for identifying the differences between EH and ER. HPLC integrated with a ß -adrenoceptor (ß -AR) activity luciferase reporter assay system was used to screen active inhibitors; molecular docking and a series of biological assays centered on ß -AR-related signaling pathways were evaluated to understand the roles of APIs. RESULTS: The opposite effect on sweating of EH and ER can be attributed to the APIs of amphetamine-type alkaloids and flavonoid derivatives. Mahuannin B is an effective anti-hydrotic agent, inhibiting the production of cAMP via suppression of adenylate cyclase (AC) activity. CONCLUSION: The effects of EH and ER on sweat and ß -AR-related signaling pathway are opposite due to different alkaloids and flavonoids of APIs in EH and ER. The present work not only sheds light on the hidroschesis action of mahuannin B, but also presents a potential target of AC in the treatment of hyperhidrosis.
[Mh] Termos MeSH primário: Inibidores de Adenilil Ciclase/farmacologia
Alcaloides/farmacologia
AMP Cíclico/metabolismo
Medicamentos de Ervas Chinesas/farmacologia
Ephedra/química
Flavonoides/farmacologia
Receptores Adrenérgicos beta 2/metabolismo
[Mh] Termos MeSH secundário: Inibidores de Adenilil Ciclase/química
Antagonistas de Receptores Adrenérgicos beta 2/química
Antagonistas de Receptores Adrenérgicos beta 2/farmacologia
Alcaloides/química
Animais
Cromatografia Líquida de Alta Pressão
Avaliação Pré-Clínica de Medicamentos/métodos
Medicamentos de Ervas Chinesas/química
Ephedra sinica/química
Efedrina/farmacologia
Flavonoides/química
Masculino
Camundongos
Simulação de Acoplamento Molecular
Receptores Adrenérgicos
Transdução de Sinais/efeitos dos fármacos
Especificidade da Espécie
Sudorese/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Adrenergic beta-2 Receptor Antagonists); 0 (Alkaloids); 0 (Drugs, Chinese Herbal); 0 (Flavonoids); 0 (Receptors, Adrenergic); 0 (Receptors, Adrenergic, beta-2); 0 (mahuannin B); E0399OZS9N (Cyclic AMP); GN83C131XS (Ephedrine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE


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[PMID]:28255005
[Au] Autor:Dessauer CW; Watts VJ; Ostrom RS; Conti M; Dove S; Seifert R
[Ad] Endereço:Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, Texas (C.W.D.); Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (V.J.W.); Department of Biomedical
[Ti] Título:International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases.
[So] Source:Pharmacol Rev;69(2):93-139, 2017 Apr.
[Is] ISSN:1521-0081
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenylyl cyclases (ACs) generate the second messenger cAMP from ATP. Mammalian cells express nine transmembrane AC (mAC) isoforms (AC1-9) and a soluble AC (sAC, also referred to as AC10). This review will largely focus on mACs. mACs are activated by the G-protein G and regulated by multiple mechanisms. mACs are differentially expressed in tissues and regulate numerous and diverse cell functions. mACs localize in distinct membrane compartments and form signaling complexes. sAC is activated by bicarbonate with physiologic roles first described in testis. Crystal structures of the catalytic core of a hybrid mAC and sAC are available. These structures provide detailed insights into the catalytic mechanism and constitute the basis for the development of isoform-selective activators and inhibitors. Although potent competitive and noncompetitive mAC inhibitors are available, it is challenging to obtain compounds with high isoform selectivity due to the conservation of the catalytic core. Accordingly, caution must be exerted with the interpretation of intact-cell studies. The development of isoform-selective activators, the plant diterpene forskolin being the starting compound, has been equally challenging. There is no known endogenous ligand for the forskolin binding site. Recently, development of selective sAC inhibitors was reported. An emerging field is the association of AC gene polymorphisms with human diseases. For example, mutations in the AC5 gene ( ) cause hyperkinetic extrapyramidal motor disorders. Overall, in contrast to the guanylyl cyclase field, our understanding of the (patho)physiology of AC isoforms and the development of clinically useful drugs targeting ACs is still in its infancy.
[Mh] Termos MeSH primário: Adenilil Ciclases/metabolismo
[Mh] Termos MeSH secundário: Inibidores de Adenilil Ciclase/farmacologia
Adenilil Ciclases/química
Animais
Seres Humanos
Conformação Proteica
Transdução de Sinais
Terminologia como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170526
[Lr] Data última revisão:
170526
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1124/pr.116.013078


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[PMID]:28253299
[Au] Autor:Shahzad H; Giribabu N; Karim K; Kassim NM; Muniandy S; Salleh N
[Ad] Endereço:Department of Physiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
[Ti] Título:Combinatorial effects of quercetin and sex-steroids on fluid and electrolytes' (Na+, Cl-, HCO3-) secretory mechanisms in the uterus of ovariectomised female Sprague-Dawley rats.
[So] Source:PLoS One;12(3):e0172765, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dysregulation of uterine fluid environment could impair successful reproduction and this could be due to the effect of environmental estrogens. Therefore, in this study, effect of quercetin, an environmental estrogen on uterine fluid and electrolytes concentrations were investigated under sex-steroid influence. Ovariectomised adult female Sprague-Dawley rats were given 10, 50 or 100mg/kg/day quercetin subcutaneously with 17-ß estradiol (E) for seven days or three days E, then three days E plus progesterone (P) (E+P) treatment. Uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations were determined by in-vivo perfusion. Following sacrifice, uteri were harvested and levels of the proteins of interest were identified by Western blotting and Realtime PCR. Distribution of these proteins in the uterus was observed by immunofluorescence. Levels of uterine cAMP were measured by enzyme-linked immunoassay (EIA). Administration of quercetin at increasing doses increased uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations, but to the levels lesser than that of E. In concordant, levels of CFTR, SLC4A4, ENaC (α, ß and γ), Na+/K+-ATPase, GPα/ß, AC and cAMP in the uterus increased following increased in the doses of quercetin. Co-administration of quercetin with E caused uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations to decrease. In concordant, uterine CFTR, SLC26A6, SLC4A4, ENaC (α, ß and γ), Na+/K+-ATPase, GPα/ß, AC and cAMP decreased. Greatest effects were observed following co-administration of 10mg/kg/day quercetin with E. Co-administration of quercetin with E+P caused uterine fluid Na+ and HCO3- concentrations to increase but no changes in fluid secretion rate and Cl- concentration were observed. Co-administration of high dose quercetin (100 mg/kg/day) with E+P caused uterine CFTR, SLC26A6, AC, GPα/ß and ENaC (α, ß and γ) to increase. Quercetin-induced changes in the uterine fluid secretion rate and electrolytes concentrations could potentially affect the uterine reproductive functions under female sex-steroid influence.
[Mh] Termos MeSH primário: Líquidos Corporais/efeitos dos fármacos
Líquidos Corporais/metabolismo
Eletrólitos/metabolismo
Hormônios Esteroides Gonadais/farmacologia
Ovariectomia
Quercetina/farmacologia
Útero/efeitos dos fármacos
[Mh] Termos MeSH secundário: Inibidores de Adenilil Ciclase
Animais
Antiporters/genética
Antiporters/metabolismo
Bicarbonatos/metabolismo
Cloretos/metabolismo
AMP Cíclico/metabolismo
Regulador de Condutância Transmembrana em Fibrose Cística/genética
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo
Interações Medicamentosas
Canais Epiteliais de Sódio/genética
Canais Epiteliais de Sódio/metabolismo
Feminino
Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo
Subunidades beta da Proteína de Ligação ao GTP/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Transporte Proteico/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
Sódio/metabolismo
Simportadores de Sódio-Bicarbonato/genética
Simportadores de Sódio-Bicarbonato/metabolismo
ATPase Trocadora de Sódio-Potássio/metabolismo
Útero/metabolismo
Útero/secreção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Antiporters); 0 (Bicarbonates); 0 (Chlorides); 0 (Electrolytes); 0 (Epithelial Sodium Channels); 0 (GTP-Binding Protein alpha Subunits); 0 (GTP-Binding Protein beta Subunits); 0 (Gonadal Steroid Hormones); 0 (Sodium-Bicarbonate Symporters); 0 (solute carrier family 26, member 6 protein, rat); 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator); 9IKM0I5T1E (Quercetin); 9NEZ333N27 (Sodium); E0399OZS9N (Cyclic AMP); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172765


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[PMID]:27992235
[Au] Autor:Deng J; Wang DX; Liang AL; Tang J; Xiang DK
[Ad] Endereço:a Department of Respiratory Medicine, Traditional Chinese Medical Hospital of Jiangbei District, Chongqing, China.
[Ti] Título:Effects of baicalin on alveolar fluid clearance and α-ENaC expression in rats with LPS-induced acute lung injury.
[So] Source:Can J Physiol Pharmacol;95(2):122-128, 2017 Feb.
[Is] ISSN:1205-7541
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:Baicalin has been reported to attenuate lung edema in the process of lung injury. However, the effect of baicalin on alveolar fluid clearance (AFC) and epithelial sodium channel (ENaC) expression has not been tested. Sprague-Dawley rats were anesthetized and intratracheally injected with either 1 mg/kg lipopolysaccharide (LPS) or saline vehicle. Baicalin with various concentrations (10, 50, and 100 mg/kg) was injected intraperitoneally 30 min before administration of LPS. Then lungs were isolated for measurement of AFC, cyclic adenosine monophosphate (cAMP) level, and cellular localization of α-ENaC. Moreover, mouse alveolar type II (ATII) epithelial cell line was incubated with baicalin (30 µmol/L), adenylate cyclase inhibitor SQ22536 (10 µmol/L), or cAMP-dependent protein kinase inhibitor (PKA) KT5720 (0.3 µmol/L) 15 min before LPS (1 µg/mL) incubation. Protein expression of α-ENaC was detected by Western blot. Baicalin increased cAMP concentration and AFC in a dose-dependent manner in rats with LPS-induced acute lung injury. The increase of AFC induced by baicalin was associated with an increase in the abundance of α-ENaC protein. SQ22536 and KT5720 prevented the increase of α-ENaC expression caused by baicalin in vitro. These findings suggest that baicalin prevents LPS-induced reduction of AFC by upregulating α-ENaC protein expression, which is activated by stimulating cAMP/PKA signaling pathway.
[Mh] Termos MeSH primário: Lesão Pulmonar Aguda/metabolismo
Canais Epiteliais de Sódio/metabolismo
Flavonoides/farmacologia
Pulmão/efeitos dos fármacos
[Mh] Termos MeSH secundário: Lesão Pulmonar Aguda/induzido quimicamente
Lesão Pulmonar Aguda/fisiopatologia
Inibidores de Adenilil Ciclase/farmacologia
Animais
Anti-Inflamatórios não Esteroides/antagonistas & inibidores
Anti-Inflamatórios não Esteroides/farmacologia
Carbazóis/farmacologia
Células Cultivadas
AMP Cíclico/metabolismo
Relação Dose-Resposta a Droga
Edema/complicações
Edema/tratamento farmacológico
Edema/fisiopatologia
Células Epiteliais/metabolismo
Células Epiteliais/fisiologia
Flavonoides/antagonistas & inibidores
Flavonoides/uso terapêutico
Ionomicina/farmacologia
Lipopolissacarídeos
Pulmão/metabolismo
Pulmão/fisiopatologia
Masculino
Camundongos
Inibidores de Proteínas Quinases/farmacologia
Pirróis/farmacologia
Ratos
Água/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Carbazoles); 0 (Epithelial Sodium Channels); 0 (Flavonoids); 0 (Lipopolysaccharides); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); 059QF0KO0R (Water); 347Q89U4M5 (baicalin); 56092-81-0 (Ionomycin); 58HV29I28S (KT 5720); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170503
[Lr] Data última revisão:
170503
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE
[do] DOI:10.1139/cjpp-2016-0212


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[PMID]:27889175
[Au] Autor:Feng H; Lu G; Li Q; Liu Z
[Ad] Endereço:The Second Hospital of Shandong University, Jinan, Shandong, China.
[Ti] Título:Inhibition of Adenylyl Cyclase in the Spinal Cord Alleviates Painful Diabetic Neuropathy in Zucker Diabetic Fatty Rats.
[So] Source:Can J Diabetes;41(2):177-183, 2017 Apr.
[Is] ISSN:2352-3840
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Diabetic neuropathy is the most common complication of both type 1 and type 2 diabetes. In this study, we tested the hypotheses that impaired Gi protein expression/function in the spinal cord is associated with the development of painful neuropathy in people with type 2 diabetes and that reduction of cyclic adenosine monophosphate (cAMP) production by inhibiting adenylyl cyclase in the spinal cord can alleviate diabetic neuropathy. METHODS: To this end, we examined the levels of cAMP, cAMP-dependent protein kinase (PKA) and cAMP response element-binding protein (CREB) in the spinal cord after the development of neuropathic pain in Zucker diabetic fatty (ZDF) rats with type 2 diabetes. We evaluated the effects of intrathecal injections of SQ22536, an adenylyl cyclase inhibitor, on mechanical allodynia and thermal hyperalgesia in rats with painful diabetic neuropathy. RESULTS: We found that diabetic ZDF rats exhibited mechanical allodynia and thermal hyperalgesia, which are associated with enhanced cAMP production, increased PKA activation and elevated CREB phosphorylation in the spinal cord. Additionally, diabetic ZDF rats exhibited attenuated expression of Giα, but not Gsα, in the spinal cord. Furthermore, intrathecal administrations of SQ22536 dose-dependently alleviated mechanical allodynia and thermal hyperalgesia in diabetic ZDF rats and reduced cAMP production, PKA activation and p-CREB expression in the spinal cord. CONCLUSIONS: Taken together, our study suggested that cAMP-mediated signalling in the spinal cord is likely critical for the development of painful neuropathy in people with type 2 diabetes.
[Mh] Termos MeSH primário: Adenina/análogos & derivados
Inibidores de Adenilil Ciclase/uso terapêutico
Diabetes Mellitus Experimental/complicações
Neuropatias Diabéticas/tratamento farmacológico
Dor/tratamento farmacológico
Medula Espinal/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adenina/administração & dosagem
Adenina/uso terapêutico
Inibidores de Adenilil Ciclase/administração & dosagem
Animais
AMP Cíclico/metabolismo
Diabetes Mellitus Experimental/tratamento farmacológico
Injeções Espinhais
Ratos Zucker
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 17318-31-9 (9-(tetrahydro-2-furyl)-adenine); E0399OZS9N (Cyclic AMP); JAC85A2161 (Adenine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161128
[St] Status:MEDLINE


  8 / 2850 MEDLINE  
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[PMID]:27667304
[Au] Autor:Tong R; Wade RC; Bruce NJ
[Ad] Endereço:Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.
[Ti] Título:Comparative electrostatic analysis of adenylyl cyclase for isoform dependent regulation properties.
[So] Source:Proteins;84(12):1844-1858, 2016 Dec.
[Is] ISSN:1097-0134
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The enzyme adenylyl cyclase (AC) plays a pivotal role in a variety of signal transduction pathways inside the cell, where it catalyzes the cyclization of adenosine triphosphate (ATP) into the second-messenger cyclic adenosine monophosphate (cAMP). Among other roles, AC regulates processes involved in neural plasticity, innervation of smooth muscles of the heart and the endocrine system of the pancreas. The functional diversity of AC is manifested in its different isoforms, each having a specific regulation pattern. There is an increasing amount of data available concerning the regulatory properties of AC isoforms, however little is known about the interactions on a structural level. Here, we conducted a comparative electrostatic analysis of the catalytic domains of all nine transmembrane AC isoforms with the aim of detecting, verifying and predicting the binding sites of molecular regulators on AC. The results provide support for the positioning of the binding site of the inhibitory protein G α at a pseudo-symmetric position to the stimulatory G α binding site. They also provide a structural interpretation of the Gßγ interaction with ACs 2, 4, and 7 and suggest a new binding site for RGS2. Comparison of the small molecule binding sites on AC shows that overall they have high electrostatic similarity, but regions of electrostatic differences are identified. These could provide a basis for the development of novel compounds with isoform-specific modulatory effects on AC. Proteins 2016; 84:1844-1858. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/química
Inibidores de Adenilil Ciclase/química
Adenilil Ciclases/química
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química
Subunidades beta da Proteína de Ligação ao GTP/química
Subunidades gama da Proteína de Ligação ao GTP/química
Proteínas RGS/química
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Sítios de Ligação
Domínio Catalítico
Seres Humanos
Isoenzimas/antagonistas & inibidores
Isoenzimas/química
Ligantes
Simulação de Dinâmica Molecular
Mutação
Ligação Proteica
Estrutura Secundária de Proteína
Bibliotecas de Moléculas Pequenas/química
Eletricidade Estática
Relação Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (GTP-Binding Protein beta Subunits); 0 (GTP-Binding Protein gamma Subunits); 0 (Isoenzymes); 0 (Ligands); 0 (RGS Proteins); 0 (RGS2 protein, human); 0 (Small Molecule Libraries); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160927
[St] Status:MEDLINE
[do] DOI:10.1002/prot.25167


  9 / 2850 MEDLINE  
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[PMID]:27547922
[Au] Autor:Ramos-Espiritu L; Kleinboelting S; Navarrete FA; Alvau A; Visconti PE; Valsecchi F; Starkov A; Manfredi G; Buck H; Adura C; Zippin JH; van den Heuvel J; Glickman JF; Steegborn C; Levin LR; Buck J
[Ad] Endereço:Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
[Ti] Título:Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
[So] Source:Nat Chem Biol;12(10):838-44, 2016 Oct.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The prototypical second messenger cAMP regulates a wide variety of physiological processes. It can simultaneously mediate diverse functions by acting locally in independently regulated microdomains. In mammalian cells, two types of adenylyl cyclase generate cAMP: G-protein-regulated transmembrane adenylyl cyclases and bicarbonate-, calcium- and ATP-regulated soluble adenylyl cyclase (sAC). Because each type of cyclase regulates distinct microdomains, methods to distinguish between them are needed to understand cAMP signaling. We developed a mass-spectrometry-based adenylyl cyclase assay, which we used to identify a new sAC-specific inhibitor, LRE1. LRE1 bound to the bicarbonate activator binding site and inhibited sAC via a unique allosteric mechanism. LRE1 prevented sAC-dependent processes in cellular and physiological systems, and it will facilitate exploration of the therapeutic potential of sAC inhibition.
[Mh] Termos MeSH primário: Inibidores de Adenilil Ciclase/farmacologia
Adenilil Ciclases/metabolismo
Pirimidinas/farmacologia
Tiofenos/farmacologia
[Mh] Termos MeSH secundário: Inibidores de Adenilil Ciclase/química
Adenilil Ciclases/química
Regulação Alostérica/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Pirimidinas/química
Solubilidade
Relação Estrutura-Atividade
Tiofenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Pyrimidines); 0 (RU-0204277); 0 (Thiophenes); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2151


  10 / 2850 MEDLINE  
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[PMID]:27402379
[Au] Autor:Seifert R
[Ad] Endereço:Institute of Pharmacology, Hannover Medical School, Hannover, Germany seifert.roland@mh-hannover.de.
[Ti] Título:Does Vidarabine Mediate Cardioprotection via Inhibition of AC5?
[So] Source:J Pharmacol Exp Ther;358(2):242-3, 2016 Aug.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is an ongoing discussion about the value of adenylyl cyclase 5 (AC5) as drug target for treatment of heart failure. This letter discusses statistical, pharmacokinetic, and pharmacodynamic reasons why the recently proposed cardioprotective effects of vidarabine cannot be readily attributed to AC5 inhibition.
[Mh] Termos MeSH primário: Inibidores de Adenilil Ciclase
Vidarabina
[Mh] Termos MeSH secundário: Adenilil Ciclases
Insuficiência Cardíaca
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); EC 4.6.1.1 (Adenylyl Cyclases); FA2DM6879K (Vidarabine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160713
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.234245



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