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β2-adrenoceptor agonist

Xingjuan Chen, Marya Meroueh, Gabriela Mazur, Evan Rouse, Karmjot Singh Hundal, Christopher W Stamatkin, Alexander G Obukhov
Regulation of uterine contractility is an important aspect of women's health. Phenylephrine, a selective agonist of the α1 -adrenoceptor and a potent smooth muscle constrictor, is widely used in women even during pregnancy to relieve cold-related symptoms, to treat postpartum haemorrhoid, and during routine eye exams. We performed isometric tension recordings to investigate the effect of phenylephrine on mouse uterine contractility. Phenylephrine decreased spontaneous and oxytocin-induced contractions in non-pregnant mouse uterine rings and strips with an IC50 of ~1 μM...
August 3, 2018: Scientific Reports
Sirirat Surinkaew, Mona Aflaki, Abhijit Takawale, Yu Chen, Xiao-Yan Qi, Marc-Antoine Gillis, Yan-Fen Shi, Jean-Claude Tardif, Nipon Chattipakorn, Stanley Nattel
Aims: Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodeling via a variety of signaling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1-signaling on LA-fibroblast (FB) function and its potential role in HF-related atrial remodeling. Methods and Results: HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP)...
July 17, 2018: Cardiovascular Research
Christopher F Rider, Mohammed O Altonsy, Mahmoud M Mostafa, Suharsh V Shah, Sarah Sasse, Martijn L Manson, Dong Yan, Carina Kärrman-Mårdh, Anna Miller-Larsson, Anthony N Gerber, Mark A Giembycz, Robert Newton
In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β 2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically relevant changes in gene expression, and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modeling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2× glucocorticoid response element (2×GRE)-driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA...
September 2018: Molecular Pharmacology
Toshihiko Ikuta, Kazumichi Fujioka, Yumi Sato, Mariko Ashina, Sachiyo Fukushima, Shohei Ohyama, Saki Okubo, Keiji Yamana, Mayumi Morizane, Kenji Tanimura, Masashi Deguchi, Kazumoto Iijima, Ichiro Morioka, Hideto Yamada
Congenital complete atrioventricular block (CCAVB) is a condition in which the atria and ventricles beat independently of each other. CCAVB cases require permanent pacemaker implantation until adulthood. Nevertheless, consensus regarding postnatal medical therapy for bradycardia has not been reached. Here we report the case of a newborn with CCAVB, whose intractable bradycardia was successfully treated with transdermal tulobuterol. Tulobuterol is a selective β2-adrenoceptor agonist, widely used safely as bronchodilator in children...
April 19, 2018: Kobe Journal of Medical Sciences
Jingyu Chen, Ying Wang, Huaxun Wu, Shangxue Yan, Yan Chang, Wei Wei
Paeoniflorin-6'- O -benzene sulfonate (CP-25) is a modified paeoniflorin, which is the main bioactive component of total glucosides of peony. This study evaluated the anti-inflammatory and immunoregulatory effects of CP-25 in mice with collagen-induced arthritis (CIA) and the potential mechanisms underlying these effects. After the onset of CIA, mice were given CP-25 (17.5, 35, or 70 mg/kg) or methotrexate (MTX, 2.0 mg/kg). The arthritis index, swollen joint count, and joint and spleen histopathology were evaluated...
2018: Frontiers in Pharmacology
Javier García-Nafría, Rony Nehmé, Patricia C Edwards, Christopher G Tate
G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of Gs to four different GPCRs have been elucidated1-4 , but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT1B receptor (5-HT1B R) bound to the agonist donitriptan and coupled to an engineered Go heterotrimer...
June 2018: Nature
Ming Zhang, Yujun Wu, Mengmeng Wang, Ying Wang, Raza Tausif, Ying Yang
Pulmonary vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which is characterized by thickening of the medial smooth muscle layer. Hypertrophy of pulmonary artery smooth muscle cells (PASMCs) participates in the development of medial thickening. Genistein can attenuate PAH and inhibit medial thickening of pulmonary arteries. Since hypoxia is one of the main causes of pulmonary hypertension, this study aims to investigate the mechanism of genistein in inhibiting hypertrophic responses in PASMCs induced by hypoxia...
May 1, 2018: Journal of Nutritional Biochemistry
Seungkirl Ahn, Biswaranjan Pani, Alem W Kahsai, Eva K Olsen, Gitte Husemoen, Mikkel Vestergaard, Lei Jin, Shuai Zhao, Laura M Wingler, Paula K Rambarat, Rishabh K Simhal, Thomas T Xu, Lillian D Sun, Paul J Shim, Dean P Staus, Li-Yin Huang, Thomas Franch, Xin Chen, Robert J Lefkowitz
Conventional drug discovery efforts at the β 2 -adrenoceptor ( β 2 AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first β 2 AR small-molecule positive allosteric modulators (PAMs)-compound (Cmpd)-6 [( R )- N -(4-amino-1-(4-( tert -butyl)phenyl)-4-oxobutan-2-yl)-5-( N -isopropyl- N -methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs...
August 2018: Molecular Pharmacology
Maria Gabriella Matera, Clive Page, Barbara Rinaldi
Inhaled selective β2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate β2-adrenergic receptors (β2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of β2-agonists to β2-AR is pleotropically coupled to many intracellular pathways whereby depending on the state of the β2-AR when activated, a subset of different intracellular responses can be triggered...
June 2018: Current Opinion in Pharmacology
Xinyue Ge, Yongmei Mo, Gang Xing, Lei Ji, Haiyan Zhao, Jianfang Chen, Bin He, Xuyao Chen, Ruijuan Xing, Xiaoqiang Li, Ying Zhao, Jinyan Li, Haining Yan, Anthony Yiu-Ho Woo, Yuyang Zhang, Bin Lin, Li Pan, Maosheng Cheng
A novel series of 2-amino-2-phenylethanol derivatives were developed as β2 -adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC50 = 0.25 nM) in stimulating β2 -adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the β1 -adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of β2 -adrenoceptor agonists...
September 2018: Bioorganic Chemistry
Xinyue Ge, Anthony Yiu-Ho Woo, Gang Xing, Yali Lu, Yongmei Mo, Ying Zhao, Yi Lan, Jinyan Li, Haining Yan, Li Pan, Yuyang Zhang, Bin Lin, Maosheng Cheng
A new series of β2 -adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC50 value of 1.26 nM in stimulating β2 -adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β2 than for the β1 subtype...
May 25, 2018: European Journal of Medicinal Chemistry
Paola Rogliani, Josuel Ora, Maria Gabriella Matera, Mario Cazzola, Luigino Calzetta
Long-acting β2 -adrenoceptor (β2 -AR) agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) is the cornerstone for treating chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations elicit clinical and functional synergistic interaction, and such an interaction should permit to reduce the dose of each monocomponent in the drug mixture to minimize the risk of adverse events (AEs). Overall, currently available LABA/LAMA fixed-dose combinations (FDCs) combine the drugs at the same doses of formulations designed for a single drug...
June 2018: Expert Opinion on Drug Safety
Qingfeng Yu, Christian Gratzke, Yiming Wang, Annika Herlemann, Frank Strittmatter, Beata Rutz, Christian G Stief, Martin Hennenberg
Alpha1-adrenoceptors induce prostate smooth muscle contraction, and hold a prominent role for pathophysiology and therapy of lower urinary tract symptoms in benign prostatic hyperplasia. G protein-coupled receptors are regulated by posttranslational regulation, including phosphorylation by G protein-coupled receptor kinases 2 and 3 (GRK2/3). Although posttranslational adrenoceptor regulation has been recently suggested to occur in the prostate, this is still marginally understood. With the newly developed CMPD101, a small molecule inhibitor with assumed specificity for GRK2/3 is now available...
July 15, 2018: European Journal of Pharmacology
Enio S A Pacini, Sarah Sanders-Silveira, Rosely O Godinho
In the respiratory tract, intracellular cAMP has a key role in the smooth muscle relaxation induced by the β 2 -adrenoceptor/Gs protein/adenylyl cyclase axis. In other tissues, cAMP also works as an extracellular messenger, after its efflux and interstitial conversion to adenosine by ectoenzymes. The aim of this study was to identify cAMP efflux and the "extracellular cAMP-adenosine pathway" in the airway smooth muscle. First, we tested the ability of β 2 -adrenoceptor agonists formoterol or fenoterol to increase the extracellular cAMP in isolated tracheal rings from adult male Wistar rats...
July 2018: Journal of Pharmacology and Experimental Therapeutics
Huaxun Wu, Jingyu Chen, Chun Wang, Lihua Liu, Yujing Wu, Yunfang Zhang, Aiwu Zhou, Lingling Zhang, Wei Wei
OBJECTIVE: To investigate the effects of β-AR signaling on fibroblast-like synoviocytes (FLS) from adjuvant-induced arthritis (AA) rats and the partial mechanisms focused on β-AR desensitization mediated by GRK2 and β-arrestin2. METHODS: Animals were divided into a control group and an AA model group, and FLSs were cultured. Arthritis index, histopathology of joints, epinephrine (Epi) and norepinephrine (NE) were detected in vivo. The effect of the β-AR agonist isoprenaline (ISO) and the β2 -AR agonist salbutamol on FLS cell viability were detected by CCK8...
April 19, 2018: Inflammopharmacology
Luigino Calzetta, Maria Gabriella Matera, Francesco Facciolo, Mario Cazzola, Paola Rogliani
BACKGROUND: Corticosteroids increase the expression of β2 -adrenoceptors (β2 -ARs) and protect them against down-regulation. Conversely, β2 -AR agonists improve the anti-inflammatory action of corticosteroids. Nevertheless, it is still uncertain whether adding a long-acting β2 -AR agonist (LABA) to an inhaled corticosteroid (ICS) results in an additive effect, or there is true synergy. Therefore, the aim of this study was to pharmacologically characterize the interaction between the ICS beclomethasone diproprionate (BDP) and the LABA formoterol fumarate (FF) in a validated human ex vivo model of bronchial asthma...
April 12, 2018: Respiratory Research
Luigino Calzetta, Maria Gabriella Matera, Mario Cazzola
Long-acting β2 adrenoceptor agonists (LABAs) in combination with long-acting muscarinic antagonists (LAMAs) can elicit functional and clinical benefits in chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations synergistically relax human isolated airways at the level of the medium and small bronchi. LABAs and LAMAs both modulate the bronchial tone via different pathways localized at the level of presynaptic parasympathetic fibers and airway smooth muscle cells. The exact nature of the interactions between these pathways is not completely understood, but there is cross-talk at many levels in airway smooth muscle cells that is also regulated by the activity of calcium-activated potassium channels and protein tyrosine kinases...
June 2018: Current Opinion in Pharmacology
Maxine J Roberts, Rebecca E Broome, Toby C Kent, Steven J Charlton, Elizabeth M Rosethorne
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF...
April 7, 2018: Respiratory Research
L Calzetta, P Rogliani, E Pistocchini, M Mattei, G Cito, P Alfonsi, C Page, M G Matera
The ultra long-acting β2 -adrenoceptor agonist olodaterol plus the ultra long-acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration-Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (1:1)...
August 2018: Journal of Veterinary Pharmacology and Therapeutics
Huimin Beng, Hao Zhang, R Jayachandra, Junxiao Li, Jie Wu, Wen Tan
Terbutaline is a β2 -adrenoceptor agonist for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Among the two isomers of terbutaline (TBT 2), R-isomer was found to be the potent enantiomer in generating therapeutic effect, while S-isomer has been reported to show side effects. In this study, R-terbutaline hydrochloride (R-TBH 6) was synthesized through chiral resolution from the racemic terbutaline sulfate (rac-TBS 1) with 99.9% enantiomeric excess (ee) in good overall yield (53.6%)...
June 2018: Chirality
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