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[PMID]: 29360121 [Au] Autor: Pregeljc D; Jug U; Mavri J; Stare J [Ad] Endereço: Theory Department, National Institute of Chemistry, Ljubljana, Slovenia. jernej.stare@ki.si. [Ti] Título: Why does the Y326I mutant of monoamine oxidase B decompose an endogenous amphetamine at a slower rate than the wild type enzyme? Reaction step elucidated by multiscale molecular simulations. [So] Source: Phys Chem Chem Phys;20(6):4181-4188, 2018 Feb 07. [Is] ISSN: 1463-9084 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: This work investigates the Y326I point mutation effect on the kinetics of oxidative deamination of phenylethylamine (PEA) catalyzed by the monoamine oxidase B (MAO B) enzyme. PEA is a neuromodulator capable of affecting the plasticity of the brain and is responsible for the mood enhancing effect caused by physical exercise. Due to a similar functionality, PEA is often regarded as an endogenous amphetamine. The rate limiting step of the deamination was simulated at the multiscale level, employing the Empirical Valence Bond approach for the quantum treatment of the involved valence states, whereas the environment (solvated protein) was represented with a classical force field. A comparison of the reaction free energy profiles delivered by simulation of the reaction in the wild type MAO B and its Y326I mutant yields an increase in the barrier by 1.06 kcal mol upon mutation, corresponding to a roughly 6-fold decrease in the reaction rate. This is in excellent agreement with the experimental kinetic studies. Inspection of simulation trajectories reveals possible sources of the point mutation effect, namely vanishing favorable electrostatic interactions between PEA and a Tyr326 side chain and an increased amount of water molecules at the active site due to the replacement of tyrosine by a less spacious isoleucine residue, thereby increasing the dielectric shielding of the catalytic environment provided by the enzyme. [Mh] Termos MeSH primário: Anfetamina/metabolismo Monoaminoxidase/metabolismo [Mh] Termos MeSH secundário: Anfetamina/química Sítios de Ligação Biocatálise Domínio Catalítico Desaminação Cinética Monoaminoxidase/química Monoaminoxidase/genética Fenetilaminas/química Fenetilaminas/metabolismo Mutação Puntual Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Phenethylamines); CK833KGX7E (Amphetamine); EC 1.4.3.4 (Monoamine Oxidase) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180124 [St] Status: MEDLINE [do] DOI: 10.1039/c7cp07069a

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[PMID]: 29352276 [Au] Autor: Osadchii OE [Ad] Endereço: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. [Ti] Título: Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals. [So] Source: PLoS One;13(1):e0191514, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates. [Mh] Termos MeSH primário: Antiarrítmicos/efeitos adversos Arritmias Cardíacas/induzido quimicamente Arritmias Cardíacas/fisiopatologia [Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos Potenciais de Ação/fisiologia Animais Fenômenos Eletrofisiológicos Feminino Flecainida/efeitos adversos Cobaias Técnicas In Vitro Perfusão Fenetilaminas/efeitos adversos Procainamida/efeitos adversos Quinidina/efeitos adversos Sulfonamidas/efeitos adversos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-Arrhythmia Agents); 0 (Phenethylamines); 0 (Sulfonamides); ITX08688JL (Quinidine); K94FTS1806 (Flecainide); L39WTC366D (Procainamide); R4Z9X1N2ND (dofetilide) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180121 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191514

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[PMID]: 29247746 [Au] Autor: Sun X; Tang L; Winesett S; Chang W; Cheng SX [Ad] Endereço: Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China; Department of Pediatrics, University of Florida, Gainesville, FL, USA. [Ti] Título: Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons. [So] Source: Life Sci;194:49-58, 2018 Feb 01. [Is] ISSN: 1879-0631 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: AIMS: Calcium-sensing receptor (CaSR) is expressed on neurons of both submucosal and myenteric plexuses of the enteric nervous system (ENS) and the CaSR agonist R568 inhibited Cl secretion in intestine. The purpose of this study was to localize the primary site of action of R568 in the ENS and to explore how CaSR regulates secretion through the ENS. MATERIALS AND METHODS: Two preparations of rat proximal and distal colon were used. The full-thickness preparation contained both the submucosal and myenteric plexuses, whereas for the "stripped" preparation the myenteric plexus with the muscle layers was removed. Both preparations were mounted onto Ussing chambers and Cl secretory responses were compared by measuring changes in short circuit current (I ). Two tissue-specific CaSR knockouts (i.e., neuron-specific vs. enterocyte-specific) were generated to compare the effect of R568 on expression of c-fos protein in myenteric neurons by immunocytochemistry. KEY FINDINGS: In full-thickness colons, tetrodotoxin (TTX) inhibited I , both in proximal and distal colons. A nearly identical inhibition was produced by R568. However, in stripped preparations, while the effect of TTX on I largely remained, the effect of R568 was nearly completely eliminated. In keeping with this, R568 reduced c-fos protein expression only in myenteric neurons of wild type mice and mutant mice that contained CaSR in neurons (i.e., Cre/Casr mice), but not in myenteric neurons of Cre/Casr mice in which neuronal cell CaSR was eliminated. SIGNIFICANCE: These results indicate that R568 exerts its anti-secretory effects predominantly via CaSR-mediated inhibition of neuronal activity in the myenteric plexus. [Mh] Termos MeSH primário: Eletrólitos/metabolismo Plexo Mientérico/efeitos dos fármacos Neurônios/efeitos dos fármacos Fenetilaminas/farmacologia Propilaminas/farmacologia Proteínas Proto-Oncogênicas c-fos/metabolismo Receptores de Detecção de Cálcio/metabolismo Bloqueadores dos Canais de Sódio/farmacologia Tetrodotoxina/farmacologia [Mh] Termos MeSH secundário: Animais Colo/efeitos dos fármacos Colo/metabolismo Masculino Camundongos Endogâmicos C57BL Plexo Mientérico/citologia Neurônios/metabolismo Ratos Sprague-Dawley [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Electrolytes); 0 (N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine); 0 (Phenethylamines); 0 (Propylamines); 0 (Proto-Oncogene Proteins c-fos); 0 (Receptors, Calcium-Sensing); 0 (Sodium Channel Blockers); 4368-28-9 (Tetrodotoxin) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180213 [Lr] Data última revisão: 180213 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171217 [St] Status: MEDLINE

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[PMID]: 29247894 [Au] Autor: Ezeoke MC; Krishnan P; Sim DS; Lim SH; Low YY; Chong KW; Lim KH [Ad] Endereço: School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, 43500, Semenyih, Selangor, Malaysia. [Ti] Título: Unusual phenethylamine-containing alkaloids from Elaeocarpus tectorius. [So] Source: Phytochemistry;146:75-81, 2018 Feb. [Is] ISSN: 1873-3700 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: From the leaves of Elaeocarpus tectorius (Lour.) Poir. four previously undescribed phenethylamine-containing alkaloids were isolated, namely, tectoricine, possessing an unprecedented isoquinuclidinone ring system incorporating a phenethylamine moiety, tectoraline, representing a rare alkamide incorporating two phenethylamine moieties, and tectoramidines A and B, representing the first naturally occurring trimeric and dimeric phenethylamine alkaloids incorporating an amidine function. The structures of these alkaloids were established by detailed spectroscopic analysis. The absolute configuration of tectoricine was determined by comparison of the experimental and calculated ECD spectra. Plausible biosynthetic pathways to the four alkaloids are proposed. [Mh] Termos MeSH primário: Alcaloides/química Elaeocarpaceae/química Fenetilaminas/química [Mh] Termos MeSH secundário: Alcaloides/isolamento & purificação Estrutura Molecular Fenetilaminas/isolamento & purificação Folhas de Planta/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Alkaloids); 0 (Phenethylamines); 327C7L2BXQ (phenethylamine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180119 [Lr] Data última revisão: 180119 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171217 [St] Status: MEDLINE

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[PMID]: 28741920 [Ti] Título: New Reliever of Jaw Pain Discovered. [So] Source: J Calif Dent Assoc;44(9):543, 2016 Sep. [Is] ISSN: 1043-2256 [Cp] País de publicação: United States [La] Idioma: eng [Mh] Termos MeSH primário: Analgésicos/uso terapêutico Dor Facial/tratamento farmacológico Arcada Osseodentária Fenetilaminas/uso terapêutico Canais de Cátion TRPV/antagonistas & inibidores Tiazóis/uso terapêutico [Mh] Termos MeSH secundário: Seres Humanos [Pt] Tipo de publicação: NEWS [Nm] Nome de substância: 0 (16-8 compound); 0 (Analgesics); 0 (Phenethylamines); 0 (TRPV Cation Channels); 0 (TRPV1 protein, human); 0 (Thiazoles) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180102 [Lr] Data última revisão: 180102 [Sb] Subgrupo de revista: D [Da] Data de entrada para processamento: 170726 [St] Status: MEDLINE

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[PMID]: 28743501 [Au] Autor: Cui C; Lin H; Shi Y; Pan R [Ad] Endereço: Department of Aesthetic Plastic Surgery and Laser Medicine, Beijing Anzhen Hospital, Capital Medical University, Anzhen Road #2, Chaoyang District, Beijing 100029, China. Electronic address: 15501008735@163.com. [Ti] Título: Hypoxic postconditioning attenuates apoptosis via inactivation of adenosine A receptor through NDRG3-Raf-ERK pathway. [So] Source: Biochem Biophys Res Commun;491(2):277-284, 2017 09 16. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: In recent years, many studies have demonstrated that endogenous adenosine induced by ischemia postconditioning reduces apoptosis in animal and cell models, but no study has clearly elucidated the effects of hypoxia postconditioning (HPC) in human dermal microvascular endothelial cells (HDMECs) of flaps, and the subtype of adenosine receptors involved remains unknown. In our study, we sought to identify the roles of adenosine A receptor, NDRG3 (N-myc downstream-regulated gene 3) and Raf-ERK pathway in the anti-apoptotic effects of hypoxia postconditioning. METHODS: Human dermal microvascular endothelial cells were put into a hypoxic incubator (94% N + 5% CO + 1% O ) for 8 h (hypoxia), and followed 24 h of normoxic culture with 95% air and 5% CO (reoxygenation). Hypoxia postconditioning model of HDMECs was achieved as follows: Before HDMECs were put into a normoxic incubator, HDMECs were treated by three cycles of 5 min of brief reoxygenation and 5 min of re-hypoxia. Opening level of mitochondrial permeability transition pore and change of mitochondrial membrane potential were detected with related Kit. The protein expressions of mitochondrion apoptosis, adenosine A receptor and NDRG3-Raf-ERK pathway were measured by western blot. RESULT: Hypoxia/reoxygenation (H/R) resulted in injury in HDMRCs as evidenced by an increase in apoptosis percentage, mitochondrial membrane permeability and an increase in expression of pro-apoptosis proteins (Bax, c-caspase-3 and cytochrom C), meanwhile, hypoxia/reoxygenation increased expression of A receptor, NDRG3, p-c-Raf, p-ERK, which was significantly attenuated by hypoxia postconditioning treatment. Moreover, Hypoxia/reoxygenation (H/R) resulted in a decrease in expression of anti-apoptotic protein (Bcl-2). However, the protective effect of hypoxia postconditioning treatment could be inhibited by adding CGS21680, a selective adenosine A receptor agonist (all P values < 0.05). [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Células Endoteliais/efeitos dos fármacos Pós-Condicionamento Isquêmico Proteínas do Tecido Nervoso/genética Oxigênio/farmacologia Receptor A2A de Adenosina/genética Quinases raf/genética [Mh] Termos MeSH secundário: Adenosina/análogos & derivados Adenosina/farmacologia Agonistas do Receptor A2 de Adenosina/farmacologia Apoptose/genética Caspase 3/genética Caspase 3/metabolismo Hipóxia Celular Derme/irrigação sanguínea Derme/citologia Derme/efeitos dos fármacos Células Endoteliais/citologia Células Endoteliais/metabolismo Regulação da Expressão Gênica Seres Humanos Sistema de Sinalização das MAP Quinases/efeitos dos fármacos Potencial da Membrana Mitocondrial Mitocôndrias/efeitos dos fármacos Mitocôndrias/metabolismo Proteínas de Transporte da Membrana Mitocondrial/genética Proteínas de Transporte da Membrana Mitocondrial/metabolismo Modelos Biológicos Proteínas do Tecido Nervoso/metabolismo Fenetilaminas/farmacologia Cultura Primária de Células Proteínas Proto-Oncogênicas c-bcl-2/genética Proteínas Proto-Oncogênicas c-bcl-2/metabolismo Receptor A2A de Adenosina/metabolismo Retalhos Cirúrgicos/irrigação sanguínea Proteína X Associada a bcl-2/genética Proteína X Associada a bcl-2/metabolismo Quinases raf/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Adenosine A2 Receptor Agonists); 0 (BAX protein, human); 0 (BCL2 protein, human); 0 (Mitochondrial Membrane Transport Proteins); 0 (NDRG3 protein, human); 0 (Nerve Tissue Proteins); 0 (Phenethylamines); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Receptor, Adenosine A2A); 0 (bcl-2-Associated X Protein); 0 (mitochondrial permeability transition pore); 120225-54-9 (2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine); EC 2.7.11.1 (raf Kinases); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3); K72T3FS567 (Adenosine); S88TT14065 (Oxygen) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171129 [Lr] Data última revisão: 171129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170727 [St] Status: MEDLINE

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[PMID]: 28873546 [Au] Autor: Qiu S; Wang Y; Cheng Y; Liu Y; Yadav MP; Yin L [Ad] Endereço: Beijing Key Laboratory for Food Non-thermal Processing, College of Food Science and Nutritional Engineering, China Agricultural University, P. O. Box 40, No. 17 Qinghuadonglu, Haidian, Beijing 100083, PR China; Eastern Regional Research Center, Agricultural Research Service, US Department of Agricul [Ti] Título: Reduction of biogenic amines in sufu by ethanol addition during ripening stage. [So] Source: Food Chem;239:1244-1252, 2018 Jan 15. [Is] ISSN: 0308-8146 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The aim of this study was to investigate the content of biogenic amines (BAs) in different types of sufu samples obtained from different producers, and the effect of ethanol in reducing BA levels during sufu ripening. The results showed that different manufacturing processes altered the distribution of BAs in commercial sufu. Putrescine, cadaverine, histamine, and tryptamine were the main and common BAs in red, white and grey sufu. The contents of putrescine, cadaverine, tryptamine, ß-phenylethylamine and tyramine in the grey sufu of all producer brands were significantly (p<0.05) higher than those in the white and red sufu. The addition of ethanol to the dressing mixture had a significant influence in reducing the total content of BAs in laboratory-made sufu. The slight increase in polypeptide and amino nitrogen contents after the addition of ethanol indicated a reduction in the degradation of water soluble protein. [Mh] Termos MeSH primário: Aminas Biogênicas/química [Mh] Termos MeSH secundário: Cadaverina Cromatografia Líquida de Alta Pressão Etanol Fenetilaminas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biogenic Amines); 0 (Phenethylamines); 327C7L2BXQ (phenethylamine); 3K9958V90M (Ethanol); L90BEN6OLL (Cadaverine) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171128 [Lr] Data última revisão: 171128 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170907 [St] Status: MEDLINE

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[PMID]: 29038104 [Au] Autor: Cho JH; Youn SJ; Moore JC; Kyriakakis R; Vekstein C; Militello M; Poe SM; Wolski K; Tchou PJ; Varma N; Niebauer MJ; Bhargava M; Saliba WI; Wazni OM; Lindsay BD; Wilkoff BL; Chung MK [Ad] Endereço: From the Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, OH. Current address for Dr Cho: Cedars-Sinai Heart Institute, Los Angeles, CA. Current address for Dr Youn: Department of Internal Medicine, Cleveland Clinic, OH. Current address for Dr Moore: Minneapolis [Ti] Título: Safety of Oral Dofetilide Reloading for Treatment of Atrial Arrhythmias. [So] Source: Circ Arrhythm Electrophysiol;10(10), 2017 Oct. [Is] ISSN: 1941-3084 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Although dofetilide labeling states that the drug must be initiated or reinitiated with continuous electrocardiographic monitoring and in the presence of trained personnel, the risks of dofetilide reloading justifying repeat hospitalization have not been investigated. METHODS AND RESULTS: Patients admitted for dofetilide reloading for atrial arrhythmias were retrospectively reviewed. The need for dose adjustment and the incidence of torsades de pointes (TdP) were identified. The incidence of TdP in dofetilide reloading was compared with patients admitted for dofetilide initial loading. Of 138 patients admitted for dofetilide reloading for atrial arrhythmias, 102 were reloaded at a previously tolerated dose, 30 with a higher dose from a previously tolerated dose and 2 at a lower dose; prior dosage was unknown in 4 patients. Dose adjustment or discontinuation was required in 44 patients (31.9%). No TdP occurred in the same dose reloading group, but TdP occurred in 2 patients admitted to increase dofetilide dosage (0% versus 6.7%; =0.050). Dofetilide dose adjustment or discontinuation was required in 30 of 102 patients (29.4%) reloaded at a previously tolerated dose and in 11 of 30 patients (36.7%) admitted for an increase in dose. CONCLUSIONS: Although no TdP occurred in patients admitted to reload dofetilide at the same dose as previously tolerated, dosage adjustments or discontinuation was frequent and support the need for hospitalization for dofetilide reloading. Patients admitted for reloading with a higher dose tended to be at higher risk for TdP than patients reloaded at a prior tolerated dose. [Mh] Termos MeSH primário: Antiarrítmicos/administração & dosagem Arritmias Cardíacas/tratamento farmacológico Frequência Cardíaca/efeitos dos fármacos Fenetilaminas/administração & dosagem Sulfonamidas/administração & dosagem [Mh] Termos MeSH secundário: Administração Oral Idoso Idoso de 80 Anos ou mais Antiarrítmicos/efeitos adversos Arritmias Cardíacas/diagnóstico Arritmias Cardíacas/fisiopatologia Esquema de Medicação Cálculos da Dosagem de Medicamento Eletrocardiografia Ambulatorial Feminino Átrios do Coração/efeitos dos fármacos Átrios do Coração/fisiopatologia Seres Humanos Masculino Registros Médicos Meia-Idade Admissão do Paciente Fenetilaminas/efeitos adversos Valor Preditivo dos Testes Estudos Retrospectivos Fatores de Risco Sulfonamidas/efeitos adversos Fatores de Tempo Torsades de Pointes/induzido quimicamente Torsades de Pointes/diagnóstico Torsades de Pointes/fisiopatologia Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Arrhythmia Agents); 0 (Phenethylamines); 0 (Sulfonamides); R4Z9X1N2ND (dofetilide) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171115 [Lr] Data última revisão: 171115 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171018 [St] Status: MEDLINE

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[PMID]: 28825813 [Au] Autor: Erli F; Guerrieri E; Ben Haddou T; Lantero A; Mairegger M; Schmidhammer H; Spetea M [Ad] Endereço: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck , Innrain 80-82, 6020 Innsbruck, Austria. [Ti] Título: Highly Potent and Selective New Diphenethylamines Interacting with the κ-Opioid Receptor: Synthesis, Pharmacology, and Structure-Activity Relationships. [So] Source: J Med Chem;60(17):7579-7590, 2017 Sep 14. [Is] ISSN: 1520-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We previously reported on a series of small molecules targeting the κ-opioid (KOP) receptor featuring a diphenethylamine scaffold and showed the promise of these ligands as effective analgesics with reduced liability for adverse effects. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds 1 (HS665) and 2 (HS666). A library of new diphenethylamines was designed, synthesized, and pharmacologically evaluated. In comparison with 1 and 2, the KOP receptor affinity, selectivity, and agonist activity were modulated by introducing bulkier N-substituents, a 2-fluoro substitution, and additional hydroxyl groups at positions 3' and 4'. Several analogues showed subnanomolar affinity and excellent KOP receptor selectivity acting as full or partial agonists, and one as an antagonist. The new diphenethylamines displayed antinociceptive efficacies with increased potencies than U50,488, 1 and 2 in the writhing assay and without inducing motor dysfunction after sc administration in mice. [Mh] Termos MeSH primário: Analgésicos/química Analgésicos/farmacologia Fenetilaminas/química Fenetilaminas/farmacologia Receptores Opioides kappa/metabolismo [Mh] Termos MeSH secundário: Analgésicos/síntese química Animais Células CHO Cricetulus Seres Humanos Masculino Camundongos Fenetilaminas/síntese química Receptores Opioides kappa/agonistas Receptores Opioides kappa/antagonistas & inibidores Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (3-(2-((cyclobutylmethyl)(phenethyl)amino)ethyl)phenol); 0 (Analgesics); 0 (Phenethylamines); 0 (Receptors, Opioid, kappa) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170822 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jmedchem.7b00981

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[PMID]: 28807491 [Au] Autor: Ahmad SF; Ansari MA; Nadeem A; Bakheet SA; Almutairi MM; Attia SM [Ad] Endereço: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: fashaikh@ksu.edu.sa. [Ti] Título: Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4 T cells from a BTBR T Itpr3tf/J mouse model of autism. [So] Source: J Neuroimmunol;311:59-67, 2017 Oct 15. [Is] ISSN: 1872-8421 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders. We investigated the effects of the A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on IL-21, IL-22, T-bet, T-box transcription factor (T-bet), GATA3 (GATA Binding Protein 3), and CD152 (CTLA-4) expression in BTBR mice. Our results showed that BTBR mice treated with SCH had increased CD4 IL-21 , CD4 IL-22 , CD4 GATA3 , and CD4 T-bet and decreased CD4 CTLA-4 expression in spleen cells compared with BTBR control mice. Moreover, CGS efficiently decreased CD4 IL-21 , CD4 IL-22 , CD4 GATA3 , and CD4 T-bet and increased CD4 CTLA-4 production in spleen cells compared with SCH-treated and BTBR control mice. Additionally, SCH treatment significantly increased the mRNA and protein expression levels of IL-21, IL-22, GATA3, and T-bet in brain tissue compared with CGS-treated and BTBR control mice. The augmented levels of IL-21/IL-22 and GATA3/T-bet could be due to altered A2AR signaling. Our results indicate that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of autistic and neuroimmune dysfunctions. [Mh] Termos MeSH primário: Transtorno Autístico/patologia Linfócitos T CD4-Positivos/metabolismo Citocinas/metabolismo Fator de Transcrição GATA3/metabolismo Receptor A2A de Adenosina/metabolismo Transdução de Sinais/genética [Mh] Termos MeSH secundário: Adenosina/análogos & derivados Adenosina/farmacologia Agonistas do Receptor A2 de Adenosina/farmacologia Antagonistas do Receptor A2 de Adenosina/farmacologia Animais Transtorno Autístico/genética Transtorno Autístico/imunologia Encéfalo/metabolismo Linfócitos T CD4-Positivos/efeitos dos fármacos Modelos Animais de Doenças Proteínas Fetais/genética Proteínas Fetais/metabolismo Regulação da Expressão Gênica/efeitos dos fármacos Regulação da Expressão Gênica/genética Receptores de Inositol 1,4,5-Trifosfato/genética Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Mutantes Neurológicos Proteínas do Tecido Nervoso/deficiência Proteínas do Tecido Nervoso/genética Fenetilaminas/farmacologia Pirimidinas/farmacologia Transdução de Sinais/efeitos dos fármacos Baço/patologia Proteínas com Domínio T-Box/genética Proteínas com Domínio T-Box/metabolismo Triazóis/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine); 0 (Adenosine A2 Receptor Agonists); 0 (Adenosine A2 Receptor Antagonists); 0 (Brachyury protein); 0 (Cytokines); 0 (Disc1 protein, mouse); 0 (Fetal Proteins); 0 (GATA3 Transcription Factor); 0 (ITPR3 protein, mouse); 0 (Inositol 1,4,5-Trisphosphate Receptors); 0 (Nerve Tissue Proteins); 0 (Phenethylamines); 0 (Pyrimidines); 0 (Receptor, Adenosine A2A); 0 (T-Box Domain Proteins); 0 (Triazoles); 120225-54-9 (2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine); K72T3FS567 (Adenosine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170816 [St] Status: MEDLINE

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