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β2-adrenoceptor agonist

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
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...
August 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
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