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β2-adrenoceptor agonist

Lotten Ragnarsson, Åsa Andersson, Walter G Thomas, Richard J Lewis
G protein-coupled receptors (GPCRs) convert extracellular stimuli to intracellular responses that regulate numerous physiological processes. Crystallographic and biophysical advances in GPCR structural analysis have aided investigations of structure-function relationships that clarify our understanding of these dynamic receptors, but the molecular mechanisms associated with activation and signaling for individual GPCRs may be more complex than was previously appreciated. Here, we investigated the proposed water-mediated, hydrogen-bonded activation switch between the conserved NPxxY motif on transmembrane helix 7 (TMH7) and a conserved tyrosine in TMH5, which contributes to α1B -adrenoceptor (α1B -AR) and β2 -AR activation...
March 12, 2019: Science Signaling
Magdalena Koziczak-Holbro, Dean F Rigel, Berengere Dumotier, David A Sykes, Jeffrey Tsao, Ngoc-Hong Nguyen, Julian Bosch, Marie Jourdain, Ludivine Flotte, Yuichiro Adachi, Michael Kiffe, Moise Azria, Robin A Fairhurst, Steven J Charlton, Brian P Richardson, Estelle Lach-Trifilieff, David J Glass, Thomas Ullrich, Shinji Hatakeyama
The anabolic effects of β2 -adrenoceptor (β2 -AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of β2 -AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived β2 -AR agonist in comparison to formoterol as a representative β2 -AR agonist which has been well characterized. In vitro, 5-HOB has nanomolar affinity for the human β2 -AR and selectivity over the β1 -AR and β3 -AR...
February 28, 2019: Journal of Pharmacology and Experimental Therapeutics
Ibrahim Ramirez-Soto, Eduardo Rodriguez, Rocío Alvarez, Eugenio Quiroz, Alicia Ortega
Carazolol (CZL) is a known agonist of β3 and antagonist of β1 and β2 adrenoceptors (AR), used in the animal production industry to improve meat quality by reducing animal stress and skeletal muscle (SM) proteolysis. Here we sought to better understand the direct effect CZL has on SM. We study CZL effect on calcium (Ca2+ ) regulation by enzymatic activity kinetics of the Ca2+ -ATPase (SERCA), in isolated sarcoplasmic reticulum (SR) from SM and on the mechanical properties of isolated muscle. In isolated SR from SM previously incubated with 0...
February 11, 2019: Cell Calcium
Gessica Marchini, Silvia Carnevali, Fabrizio Facchinetti
Cigarette smokers with asthma and chronic obstructive pulmonary disease (COPD) are less responsive to glucocorticoids (GCs). The anti-inflammatory action of GCs depends also on their ability to transactivate genes such as GC-induced leucine zipper (GILZ). We investigated the effects of aqueous cigarette smoke extract (CSE) on GILZ transactivation evoked by 17-beclomethasone monopropionate (BMP) or fluticasone propionate (FP) in the presence or absence of the long acting β2-adrenoceptor agonist (LABA) bronchodilator formoterol or salmeterol in human primary cultures of human bronchial smooth muscle cells (HBSMC)...
February 10, 2019: European Journal of Pharmacology
Anthony Yiu-Ho Woo, Xin-Yue Ge, Li Pan, Gang Xing, Yong-Mei Mo, Rui-Juan Xing, Xiao-Ran Li, Yu-Yang Zhang, Irving W Wainer, Mao-Sheng Cheng, Rui-Ping Xiao
β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects...
January 14, 2019: Acta Pharmacologica Sinica
Javier Milara, Sonia Contreras, Alfredo de Diego, Marta Calbet, Mònica Aparici, Esteban Morcillo, Montserrat Miralpeix, Julio Cortijo
Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and β2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and β2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients...
2019: PloS One
Yu-Shan She, Li-Qun Ma, Bei-Bei Liu, Wen-Jing Zhang, Jun-Ying Qiu, Yuan-Yuan Chen, Meng-Yue Li, Lu Xue, Xi Luo, Qian Wang, Hao Xu, Dun-An Zang, Xiao-Xue Zhao, Lei Cao, Jinhua Shen, Yong-Bo Peng, Ping Zhao, Meng-Fei Yu, Weiwei Chen, Xiaowei Nie, Chenyou Shen, Shu Chen, Shanshan Chen, Gangjian Qin, Jiapei Dai, Jingyu Chen, Qing-Hua Liu
β2 -adrenoceptor agonists are commonly used as bronchodilators to treat obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), however, they induce severe side effects. Therefore, developing new bronchodilators is essential. Herbal plants were extracted and the extracts' effect on airway smooth muscle (ASM) precontraction was assessed. The ethyl alcohol extract of semen cassiae (EESC) was extracted from Semen cassia . The effects of EESC on the ACh- and 80 mM K+ -induced sustained precontraction in mouse and human ASM were evaluated...
2018: Frontiers in Pharmacology
Jolanta Weresa, Anna Pędzińska-Betiuk, Rafał Kossakowski, Barbara Malinowska
BACKGROUND: Drugs targeting CB1 and CB2 receptors have been suggested to possess therapeutic benefit in cardiovascular disorders associated with elevated sympathetic tone. Limited data suggest cannabinoid ligands interact with postsynaptic β-adrenoceptors. The aim of this study was to examine the effects of CB1 and CB2 antagonists, AM251 and AM630, respectively, at functional cardiac β-adrenoceptors. METHODS: Experiments were carried out in isolated spontaneously beating right atria and paced left atria where inotropic and chronotropic increases were induced by isoprenaline and selective agonists of β1 and β2 -adrenergic receptors...
September 17, 2018: Pharmacological Reports: PR
Roberto T Sudo, Kenichiro Hayashida, Aluizio N Santos, Masahito Kawatani, Carlos Es Monteiro, Roberto D Moreira, Margarete M Trachez, Guilherme C Montes, Gisele Zapata-Sudo
Objective: To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective α4 β2 * nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models. Materials and methods: Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods...
2018: Journal of Pain Research
Marvin A Soriano-Ursúa, Martiniano Bello, Christian F Hernández-Martínez, Iván Santillán-Torres, Ruth Guerrero-Ramírez, José Correa-Basurto, José-Antonio Arias-Montaño, José G Trujillo-Ferrara
The design of beta2 adrenoceptor (β2 AR) agonists is attractive because of their wide-ranging applications in medicine, and the details of agonist interactions with β2 AR are interesting because it is considered a prototype for G-protein coupled receptors. Preclinical studies for agonist development have involved biological assays with guinea pigs due to a similar physiology to humans. Boron-containing Albuterol derivatives (BCADs) designed as bronchodilators have improved potency and efficacy compared with their boron-free precursor on guinea pig β2 ARs (gpβ2 ARs), and two of the BCADs (BR-AEA and boronterol) conserve these features on cells expressing human β2 ARs (hβ2 ARs)...
November 1, 2018: European Biophysics Journal: EBJ
Hideyasu Yamada, Norihito Hida, Nobuyuki Hizawa
Background: A large body of evidence suggests that long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) combinations induce a strong synergistic bronchodilatory effect in human isolated airways. Moreover, a recent post hoc analysis demonstrated clinical synergism between LABAs and LAMAs, which induces a synergistic improvement not only in lung function but also in dyspnea in COPD patients. Aim: The aim of this study is to examine the baseline factors related to improvement in lung function or clinical symptoms that results from the administration of LAMA or LAMA/LABA and to compare the differences in improvement in lung function or clinical symptoms between LAMA and LAMA/LABA...
2018: International Journal of Chronic Obstructive Pulmonary Disease
Emilio J Vélez, Sara Balbuena-Pecino, Encarnación Capilla, Isabel Navarro, Joaquim Gutiérrez, Miquel Riera-Codina
β2 -adrenoceptors are a subtype of G-protein coupled receptors whose activation leads to increased protein synthesis and decreased degradation in mammalian skeletal muscle, causing hypertrophy. In this study, we compared the effects of the classical β2 -agonist noradrenaline (NA) with two representatives of a new generation of agonists (formoterol, FOR and salmeterol, SALM) on growth and metabolism of primary cultured muscle cells of gilthead sea bream. Activation of signaling pathways, cell development and expression of relevant genes were analyzed in day 4 myocytes...
October 19, 2018: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
Naomi Gronich, Darrell R Abernethy, Eitan Auriel, Idit Lavi, Gad Rennert, Walid Saliba
BACKGROUND: β2-adrenoreceptors have recently been identified as regulators of the α-synuclein gene, which is implicated in the pathogenesis of Parkinson's disease. OBJECTIVE: The objectives of this study were to assess the association between use of β2-agonists and β-antagonists and the risk of developing PD. METHODS: We conducted a nested case-control study in a cohort of 1,762,164 adults without a diagnosis of PD. They were identified on January, 1, 2004, from the electronic medical records of the largest health care provider in Israel...
September 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Andrea S Melani
Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 µg, a long-acting β2-adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy. Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD. Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use...
October 12, 2018: Expert Opinion on Pharmacotherapy
Weijia Zhou, Jixia Wang, Yaopeng Zhao, Long Yu, Ye Fang, Hongli Jin, Han Zhou, Pengyu Zhang, Yanfang Liu, Xiuli Zhang, Xinmiao Liang
Traditional Chinese Medicines (TCMs) have been widely used in clinical practice, and provided a rich source for discovering new drug leads. However, efficient identification of active molecules responsible for the therapeutic effects of complex TCMs is still highly challenging. Here, we combined label-free cell phenotypic assay with two dimensional liquid chromatography (2DLC) to identify potential β2 -adrenoceptor (β2 -AR) agonists related to anti-asthmatic effect of Curcuma zedoaria Rosc (C.zedoaria), a commonly used TCM...
November 23, 2018: Journal of Chromatography. A
Tresa George, Mainak Chakraborty, Mark A Giembycz, Robert Newton
Background: Asthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and inflammation. Common asthma therapeutics up-regulate expression of the regulator of G protein signalling (RGS), RGS2. As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase-activating protein in an acute neutrophilic model of lung inflammation...
2018: Allergy, Asthma, and Clinical Immunology
Ryou Kubota, Wataru Nomura, Takuma Iwasaka, Kento Ojima, Shigeki Kiyonaka, Itaru Hamachi
Investigating individual G-protein-coupled receptors (GPCRs) involved in various signaling cascades can unlock a myriad of invaluable physiological findings. One of the promising strategies for addressing the activity of each subtype of receptor is to design chemical turn-on switches on the target receptors. However, valid methods to selectively control class A GPCRs, the largest receptor family encoded in the human genome, remain limited. Here, we describe a novel approach to chemogenetically manipulate activity of engineered class A GPCRs carrying a His4 tag, using metal complex-agonist conjugates (MACs)...
September 26, 2018: ACS Central Science
Johsuke Hara, Kazuo Kasahara, Noriyuki Ohkura, Kenta Yamamura, Tamami Sakai, Miki Abo, Naohiko Ogawa, Keigo Saeki, Hayato Koba, Satoshi Watanabe, Yuka Uchida, Yuichi Tambo, Takashi Sone, Hideharu Kimura
OBJECTIVE: In Japan, most asthma deaths occur among the elderly. We should improve the control of asthma in elderly patients to reduce the number of deaths due to asthma. This retrospective study aimed to evaluate the efficacy of tiotropium RespimatⓇ (Tio-Res) in symptomatic, never-smoking, elderly asthmatics with irreversible airflow limitation despite the use of high-dose inhaled corticosteroids (ICS) plus long-acting β2 -adrenoceptor agonists (LABA). METHODS: The Asthma Control Test™ (ACT), pulmonary function tests, morning and evening peak flow (mPEF, ePEF, respectively, evaluated with an ASSESS® peak flow meter), and respiratory impedance (assessed with MostGraph® ) were measured before and after a minimum of one year of Tio-Res 5 µg/day administration...
September 7, 2018: Drug Research
Dana S Hutchinson, Nadine Brew, Teresa Vu, Jon Merlin, Nadia Hale, David William Walker, Flora Y Wong
Preterm infants frequently suffer cardiovascular compromise, with hypotension and/or low systemic blood flow, leading to tissue hypoxia-ischemia (HI). Many preterm infants respond inadequately to inotropic treatments using adrenergic agonists such as dobutamine or dopamine. This may be due to altered cardiac adrenoceptor expression due to tissue HI, or prolonged exposure to adrenergic agonists. We assessed the effects of severe HI with and without dobutamine/dopamine treatment on cardiac adrenoceptor expression in preterm fetal sheep...
August 23, 2018: Journal of Applied Physiology
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
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