Alpha-2 Adrenergic Agonists R15
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Molecular Signatures of G-Protein-Coupled Receptors A
REVIEW doi:10.1038/nature11896 Molecular signatures of G-protein-coupled receptors A. J. Venkatakrishnan1, Xavier Deupi2, Guillaume Lebon1,3,4,5, Christopher G. Tate1, Gebhard F. Schertler2,6 & M. Madan Babu1 G-protein-coupled receptors (GPCRs) are physiologically important membrane proteins that sense signalling molecules such as hormones and neurotransmitters, and are the targets of several prescribed drugs. Recent exciting developments are providing unprecedented insights into the structure and function of several medically important GPCRs. Here, through a systematic analysis of high-resolution GPCR structures, we uncover a conserved network of non-covalent contacts that defines the GPCR fold. Furthermore, our comparative analysis reveals characteristic features of ligand binding and conformational changes during receptor activation. A holistic understanding that integrates molecular and systems biology of GPCRs holds promise for new therapeutics and personalized medicine. ignal transduction is a fundamental biological process that is comprehensively, and in the process expand the current frontiers of required to maintain cellular homeostasis and to ensure coordi- GPCR biology. S nated cellular activity in all organisms. Membrane proteins at the In this analysis, we objectively compare known structures and reveal cell surface serve as the communication interface between the cell’s key similarities and differences among diverse GPCRs. We identify a external and internal environments. One of the largest and most diverse consensus structural scaffold of GPCRs that is constituted by a network membrane protein families is the GPCRs, which are encoded by more of non-covalent contacts between residues on the transmembrane (TM) than 800 genes in the human genome1. GPCRs function by detecting a helices. -
Emerging Evidence for a Central Epinephrine-Innervated A1- Adrenergic System That Regulates Behavioral Activation and Is Impaired in Depression
Neuropsychopharmacology (2003) 28, 1387–1399 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Perspective Emerging Evidence for a Central Epinephrine-Innervated a1- Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression ,1 1 1 1 1 Eric A Stone* , Yan Lin , Helen Rosengarten , H Kenneth Kramer and David Quartermain 1Departments of Psychiatry and Neurology, New York University School of Medicine, New York, NY, USA Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain a1B-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain a -adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups 1 or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and a are restored by a number of antidepressants. This ‘EPI- 1 system’ may therefore represent a new target system for this disorder. Neuropsychopharmacology (2003) 28, 1387–1399, advance online publication, 18 June 2003; doi:10.1038/sj.npp.1300222 Keywords: a1-adrenoceptors; epinephrine; motor activity; depression; inactivity INTRODUCTION monoaminergic systems. This new system appears to be impaired during stress and depression and thus may Depressive illness is currently believed to result from represent a new target for this disorder. -
Dexmedetomidine)
Frequently asked questions regarding alpha-2 agonist DEXDOMITOR® (dexmedetomidine) Q: How should I monitor a patient that has received DEXDOMITOR for sedation or as a premedication? A: The monitoring of vital signs is critical for any patient under sedation or anesthesia. It is important to monitor heart rate, blood pressure, palpable pulse quality, and respiratory rate and volume. Because a2 agonists cause peripheral vasoconstriction, the use of pulse oximetry may not adequately reflect the true status of the patient. Q: What can I expect to see in a patient under DEXDOMITOR sedation? A: The patient may have pale pink or grayish mucous membranes because of peripheral vasoconstriction. The sedation induced by DEXDOMITOR causes a decrease in respiratory rate and a lower body temperature. Q: What is considered a low heart rate? A: Because of the wide range of dog sizes and corresponding heart rates, normal heart rates should be based on the dog’s body size. A reduction in heart rate following a2 agonist sedation should be expected. Patient status should be evaluated by the simultaneous measurement of many parameters, including pulse quality, respiratory rate and quality, blood pressure, and heart rate. Q: What is the effect on the respiratory rate? A: DEXDOMITOR does not have a direct effect on respiration. Although the respiratory rate may decrease as a result of sedation, ventilatory volume generally increases, and overall ventilation (gas exchange) remains stable. Q: I am concerned about hypothermia. A: Hypothermia can occur in a patient following administration of any anesthetic or sedative drug. It is important that body temperature be maintained in all patients undergoing anesthesia or sedation, including those that receive an a2 agonist. -
Covalent Agonists for Studying G Protein-Coupled Receptor Activation
Covalent agonists for studying G protein-coupled receptor activation Dietmar Weicherta, Andrew C. Kruseb, Aashish Manglikb, Christine Hillera, Cheng Zhangb, Harald Hübnera, Brian K. Kobilkab,1, and Peter Gmeinera,1 aDepartment of Chemistry and Pharmacy, Friedrich Alexander University, 91052 Erlangen, Germany; and bDepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Brian K. Kobilka, June 6, 2014 (sent for review April 21, 2014) Structural studies on G protein-coupled receptors (GPCRs) provide Disulfide-based cross-linking approaches (17, 18) offer important insights into the architecture and function of these the advantage that the covalent binding of disulfide-containing important drug targets. However, the crystallization of GPCRs in compounds is chemoselective for cysteine and enforced by the active states is particularly challenging, requiring the formation of affinity of the ligand-pharmacophore rather than by the elec- stable and conformationally homogeneous ligand-receptor com- trophilicity of the cross-linking function (19). We refer to the plexes. Native hormones, neurotransmitters, and synthetic ago- described ligands as covalent rather than irreversible agonists nists that bind with low affinity are ineffective at stabilizing an because cleavage may be promoted by reducing agents and the active state for crystallogenesis. To promote structural studies on disulfide transfer process is a reversible chemical reaction the pharmacologically highly relevant class -
Volume 25, Issue 8 April 23, 2020
April 23, 2020 Volume 25 Issue 8 SPECIAL EDITION COVID-19 Error-prone dose expression on label of COVID-19 Collaboration unapproved drug, ascorbic acid, from Mylan Tripping on extension tubing PROBLEM : A pharmacist received an order for 500 mg of intravenous (IV) ascorbic A COVID-19 patient was being treated in acid for a patient with coronavirus (COVID-19). Although this product was on an intensive care unit (ICU) in a negative formulary at the hospital, it was rarely used prior to the COVID-19 pandemic, and pressure room. An ICU nurse had seen a the pharmacist had never dispensed it. (In COVID-19 investigational trials, IV ascorbic post on social media about another facility acid is being used in much larger doses placing smart infusion pumps outside of [i.e., 10 or 12 g] after being added to an patient rooms to help minimize the use of appropriate diluent, with the theory that it personal protective equipment (PPE). She will hasten recovery.) decided to implement this workflow. She moved the infusion pump to an anteroom After selecting the available vial of ascorbic outside the patient’s negative pressure acid injection (Mylan), the pharmacist room, and used extension sets to run the noticed that the principal display panel on tubing under the door and to the patient. the carton and vial label indicated that it The patient was receiving intravenous contained 500 mg/mL ( Figure 1 ). This is in (IV) norepinephrine via the infusion pump conflict with USP <7>, which requires most to treat hypotension. The extension tubing medication labels to list the total amount of was on the floor and not secured to drug and volume in the vial (with the per Figure 1. -
Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss
Supplemental Material can be found at: /content/suppl/2020/12/18/73.1.202.DC1.html 1521-0081/73/1/202–277$35.00 https://doi.org/10.1124/pharmrev.120.000056 PHARMACOLOGICAL REVIEWS Pharmacol Rev 73:202–277, January 2021 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: MICHAEL NADER Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanismss Antonio Inserra, Danilo De Gregorio, and Gabriella Gobbi Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada Abstract ...................................................................................205 Significance Statement. ..................................................................205 I. Introduction . ..............................................................................205 A. Review Outline ........................................................................205 B. Psychiatric Disorders and the Need for Novel Pharmacotherapies .......................206 C. Psychedelic Compounds as Novel Therapeutics in Psychiatry: Overview and Comparison with Current Available Treatments . .....................................206 D. Classical or Serotonergic Psychedelics versus Nonclassical Psychedelics: Definition ......208 Downloaded from E. Dissociative Anesthetics................................................................209 F. Empathogens-Entactogens . ............................................................209 -
Original Research Bethanecol Chloride for Treatment of Clomipramine
REV. HOSP. CLÍN. FAC. MED. S. PAULO 59(6):357-360, 2004 ORIGINAL RESEARCH BETHANECOL CHLORIDE FOR TREATMENT OF CLOMIPRAMINE-INDUCED ORGASMIC DYSFUNCTION IN MALES Márcio Bernik, Antonio Hélio Guerra Vieira and Paula Villela Nunes BERNIK M et al. Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males. Rev. Hosp. Clin. Fac. Med. S. Paulo 59(6):357-360, 2004. PURPOSE: To investigate whether bethanecol chloride may be an alternative for the clinical management of clomipramine-induced orgasmic dysfunction, reported to occur in up to 96% of male users. METHODS: In this study, 12 fully remitted panic disorder patients, complaining of severe clomipramine-induced ejaculatory delay, were randomly assigned to either bethanecol chloride tablets (20 mg, as needed) or placebo in a randomized, double-blind, placebo-controlled, two-period crossover study. A visual analog scale was used to assess severity of the orgasmic dysfunction. RESULTS: A clear improvement was observed in the active treatment period. No placebo or carry-over effects were observed. CONCLUSION: These findings suggest that bethanecol chloride given 45 minutes before sexual intercourse may be useful for clomipramine-induced orgasmic dysfunction in males. KEYWORDS: Orgasmic dysfunction. Clomipramine. Bethanecol chloride. Panic disorder. Pharmacological treatment. In panic disorder patients, effective clude the following: 1) increased brain side effects such as orgasmic dysfunc- pharmacological treatment with anti- serotonin, particularly affecting 5TH2 tion in up to 20% to 96% of pa- depressants has been shown to greatly and 5HT3 receptors; 2) decreased tients.5,6,13 improve the quality of life, but it is of- dopamine; 3) central blockade of Clomipramine is the imipramine ten associated with the emergence of cholinergic and alpha-1 adrenergic analogue of chlorpromazine. -
Dr Michael Crowley Professor Malcolm Dando
DOWN THE SLIPPERY SLOPE? A STUDY OF CONTEMPORARY DUAL-USE CHEMICAL AND LIFE SCIENCE RESEARCH POTENTIALLY APPLICABLE TO INCAPACITATING CHEMICAL AGENT WEAPONS BIOCHEMICAL SECURITY 2030 POLICY PAPER SERIES NUMBER 8 BIOCHEMICAL SECURITY 2030 PROJECT BRADFORD NON-LETHAL WEAPONS RESEARCH PROJECT OCTOBER 2014 Dr Michael Crowley Project Coordinator of the Bradford Non-Lethal Weapons Research Project based at the Peace Studies Department, School of Social and International Studies, University of Bradford, United Kingdom. Email: [email protected] Professor Malcolm Dando School of Social and International Studies University of Bradford, Bradford Email: [email protected] ACKNOWLEDGEMENTS The authors, as well as the Biochemical Security 2030 Project organisers, would like to thank those who have reviewed or commented upon drafts of this report. In particular this includes Professor Julian Perry Robinson and Dr Ralf Trapp as well as others, including those members of the Biochemical Security 2030 expert panel, who commented on this document. We are also grateful to those Government officials, named and unnamed, who have replied to our information requests and/or commented upon specific sections of this report. We are grateful to the Economic and Social Research Council as well as the Defence Science and Technology Laboratory Futures and Innovation Domain for funding the Biochemical Security 2030 Project. The authors would also like to express their gratitude to the Joseph Rowntree Charitable Trust for their financial support for aspects of this research. The research findings and policy recommendations detailed in this publication have been developed under the auspices of the Bradford Non-Lethal Weapons Research Project (BNLWRP) and reflect the organisation's position on these issues. -
PRODUCT MONOGRAPH PRECEDEX® Dexmedetomidine
PRODUCT MONOGRAPH PRECEDEX® Dexmedetomidine Hydrochloride for Injection 100 mcg/mL dexmedetomidine (as dexmedetomidine hydrochloride) (Concentrate, 2 mL vial) Dexmedetomidine Hydrochloride Injection 4 mcg/mL dexmedetomidine (as dexmedetomidine hydrochloride) (Ready to use, 20 mL, 50 mL and 100 mL vials) Alpha2-adrenergic agonist Pfizer Canada ULC Date of Revision: 17300 Trans-Canada Highway July 2, 2020 Kirkland, Québec H9J 2M5 Submission Control No.: 237805 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE ..............................................................................3 CONTRAINDICATIONS ...................................................................................................4 WARNINGS AND PRECAUTIONS ..................................................................................4 ADVERSE REACTIONS ....................................................................................................8 DRUG INTERACTIONS ..................................................................................................12 DOSAGE AND ADMINISTRATION ..............................................................................13 OVERDOSAGE ................................................................................................................15 ACTION AND CLINICAL PHARMACOLOGY ............................................................16 -
Age-Associated Reductions in Cardiac Beta1- and Beta2- Adrenergic Responses Without Changes in Inhibitory G Proteins Or Receptor Kinases
Age-associated reductions in cardiac beta1- and beta2- adrenergic responses without changes in inhibitory G proteins or receptor kinases. R P Xiao, … , E G Lakatta, W J Koch J Clin Invest. 1998;101(6):1273-1282. https://doi.org/10.1172/JCI1335. Research Article While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern beta-AR signaling must still be examined in aged hearts. Specifically, the contribution of beta- AR subtypes (beta1 versus beta2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (Gi) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished beta-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both beta1-AR and beta2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both beta-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both beta-AR subtypes and a reduction in membrane adenylyl cyclase response to both beta- AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either beta1- AR or beta2-AR stimulation were not rescued by inhibiting Gi with pertussis toxin treatment. -
Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders
Neuropsychopharmacology (2003) 28, 402–412 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders ,1 2 3 2 Gerard J Marek* , Linda L Carpenter , Christopher J McDougle and Lawrence H Price 1Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 2Department of Psychiatry and Human, Brown Medical School, Mood 3 Disorders Program, Behavior, Butler Hospital, Providence, RI, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT antagonists may also be effective in 2 ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT receptor activation. These clinical and preclinical observations suggest that the combination of highly 2A selective 5-HT antagonists and SSRIs, as well as strategies to combine high-potency 5-HT receptor and 5-HT transporter blockade in 2A 2A a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders. -
Structural Features of Β2 Adrenergic Receptor
Mol. Cells 2015; 38(2): 105-111 http://dx.doi.org/10.14348/molcells.2015.2301 Molecules and Cells http://molcells.org Established in 1990 Structural Features of 2 Adrenergic Receptor: Crystal Structures and Beyond Injin Bang, and Hee-Jung Choi* The beta2-adrenergic receptor (2AR) belongs to the G class A, also referred to as rhodopsin type GPCRs. In 2000, the protein coupled receptor (GPCR) family, which is the larg- first GPCR structure was visualized by using bovine rhodopsin est family of cell surface receptors in humans. Extra atten- complexed with 11-cis-retinal and this structure has been used tion has been focused on the human GPCRs because they as an important template for GPCR modeling (Palczewski et al., have been studied as important protein targets for phar- 2000). The overall rhodopsin structure consists of seven trans- maceutical drug development. In fact, approximately 40% membrane (TM) helices and three loop regions at the extracel- of marketed drugs directly work on GPCRs. GPCRs re- lular and the cytoplasmic sides. The ligand binding pocket of spond to various extracellular stimuli, such as sensory rhodopsin is formed by hydrophobic residues from TM5 and signals, neurotransmitters, chemokines, and hormones, to TM6 to stabilize the hydrocarbone backbone of retinal, which is induce structural changes at the cytoplasmic surface, ac- covalently bound to Lys296 of TM7. tivating downstream signaling pathways, primarily through One of the common sequence motifs in rhodopsin type interactions with heterotrimeric G proteins or through G- GPCRs is the D[E]RY motif on TM3, which forms an ionic lock protein independent pathways, such as arrestin.