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Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation In
Graduate Physical and Life Sciences PhD Pharmacology Abstract ID# 1081 Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation in Drug Abuse? Fleischer, Lisa M; Tamashunas, Nina and Miller, Gregory M Addiction Sciences Laboratory, Northeastern University, Boston MA 02115 Abstract Discovered in 2001, Trace Amine Associated Receptor 1 (TAAR1) is a direct target of Data and Results amphetamine, methamphetamine and MDMA. It is expressed in the brain reward circuity and modulates dopamine transporter function and dopamine neuron firing rates. Newly-developed compounds that specifically target TAAR1 have recently been investigated in animal models In addition to brain, TAAR1 is expressed in immune cells METH promotes PKA and PKC Phosphorylation through TAAR1 as candidate therapeutics for methamphetamine, cocaine and alcohol abuse. These studies • We treated HEK/TAAR1 cells and HEK293 involving classic behavioral measures of drug response, as well as drug self-administration, Rhesus and Human cells with vehicle or METH, with and without strongly implicate TAAR1 as a potential therapeutic target for the treatment of addiction. In activators and inhibitors of PKA and PKC. addition to its central actions, we demonstrated that TAAR1 is upregulated in peripheral blood Cells Lines mononuclear cells (PBMC) and B cells following immune activation, and that subsequent • We performed Western blotting experiments to activation of TAAR1 by methamphetamine stimulates cAMP, similar to the function of measure levels of phospho-PKA and phospho- adenosine A2 receptors which are also present in immune cells and play a critical role in the PKC. immune response. Here, we are investigating the relationship between TAAR1 and the • We found that specific activators of PKA and adenosine A2 receptor at the level of cellular signaling and receptor dimerization. -
Certificate of Analysis
Print Date: Jan 3rd 2020 Certificate of Analysis www.tocris.com Product Name: EPPTB Catalog No.: 4518 Batch No.: 1 CAS Number: 1110781-88-8 IUPAC Name: N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide 1. PHYSICAL AND CHEMICAL PROPERTIES Batch Molecular Formula: C20H21F3N2O2 Batch Molecular Weight: 378.39 Physical Appearance: White solid Solubility: DMSO to 100 mM ethanol to 100 mM Storage: Store at +4°C Batch Molecular Structure: 2. ANALYTICAL DATA TLC: Rf = 0.2 (Ethyl acetate:Petroleum ether [4:1]) HPLC: Shows 99.9% purity 1H NMR: Consistent with structure Mass Spectrum: Consistent with structure Microanalysis: Carbon Hydrogen Nitrogen Theoretical 63.48 5.59 7.4 Found 63.37 5.53 7.44 Caution - Not Fully Tested • Research Use Only • Not For Human or Veterinary Use bio-techne.com North America China Europe Middle East Africa Rest of World [email protected] Tel: (800) 343 7475 [email protected] Tel: +44 (0)1235 529449 www.tocris.com/distributors [email protected] Tel: +86 (21) 52380373 Tel:+1 612 379 2956 Print Date: Jan 3rd 2020 Product Information www.tocris.com Product Name: EPPTB Catalog No.: 4518 Batch No.: 1 CAS Number: 1110781-88-8 IUPAC Name: N-(3-Ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide Description: Storage: Store at +4°C Trace amine 1 (TA ) receptor antagonist/inverse agonist; 1 Solubility & Usage Info: exhibits a higher potency at the mouse TA1 receptor than the rat DMSO to 100 mM and human TA150 receptors (IC values are 27.5, 4539 and 7487 ethanol to 100 mM nM, respectively). -
Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation K
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by FarFar - Repository of the Faculty of Pharmacy, University of Belgrade REVIEW Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation K. Nikolic & D. Agbaba Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe, Belgrade, Serbia Keywords SUMMARY α2-Adrenergic receptors; Centrally acting antihypertensives; Clonidine; Hypertension; Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in Imidazoline receptors; Rilmenidine. the mechanism of action of some centrally acting antihypertensives has received tremen- dous attention. To date, pharmacological studies have allowed the characterization of three Correspondence main imidazoline receptor classes, the I1-imidazoline receptor which is involved in central K. Nikolic, Faculty of Pharmacy, Institute of inhibition of sympathetic tone to lower blood pressure, the I2-imidazoline receptor which Pharmaceutical Chemistry, University of is an allosteric binding site of monoamine oxidase B (MAO-B), and the I3-imidazoline re- Belgrade, Vojvode Stepe 450, 11000 Belgrade, ceptor which regulates insulin secretion from pancreatic β-cells. All three imidazoline re- Serbia. ceptors represent important targets for cardiovascular research. The hypotensive effect of + Tel: 381-63-84-30-677; clonidine-like centrally acting antihypertensives was attributed both to α2-adrenergic re- + Fax: 381-11-3974-349; ceptors and nonadrenergic I1-imidazoline receptors, whereas their sedative action involves E-mail: [email protected] activation of only α2-adrenergic receptors located in the locus coeruleus. Since more selec- tive I1-imidazoline receptors ligands reduced incidence of typical side effects of other cen- trally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I1-imidazoline receptors. -
Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission
The Journal of Neuroscience, October 14, 2015 • 35(41):14057–14069 • 14057 Neurobiology of Disease Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission Alexandra Alvarsson,1* Xiaoqun Zhang,1* Tiberiu L Stan,1 Nicoletta Schintu,1 Banafsheh Kadkhodaei,2 Mark J. Millan,3 Thomas Perlmann,2,4 and Per Svenningsson1 1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden, 2Ludwig Institute for Cancer Research, SE-17177 Stockholm, Sweden, 3Pole of Innovation in Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris 87290, France, and 4Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden Parkinson’s disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes dyskinesia. Trace Amine-Associated Receptor 1 (TAAR1) modulates dopaminergic transmission, but its role in experimental Parkinsonism and L-DOPA responses has been neglected. Here, we report that TAAR1 knock-out (KO) mice show a reduced loss of dopaminergic markers in response to intrastriatal 6-OHDA administra- tion compared with wild-type (WT) littermates. In contrast, the TAAR1 agonist RO5166017 aggravated degeneration induced by intra- striatal6-OHDAinWTmice.Subchronic L-DOPAtreatmentofTAAR1KOmiceunilaterallylesionedwith6-OHDAinthemedialforebrain bundle resulted in more pronounced rotational behavior and dyskinesia than in their WT counterparts. The enhanced behavioral sensitization to L-DOPA in TAAR1 KO mice was paralleled by increased phosphorylation of striatal GluA1 subunits of AMPA receptors. Conversely, RO5166017 counteracted both L-DOPA-induced rotation and dyskinesia as well as AMPA receptor phosphorylation. -
Effects of the Trace Amine Associated Receptor 1 Agonist RO5263397 On
International Journal of Neuropsychopharmacology, 2015, 1–7 doi:10.1093/ijnp/pyu060 Research Article research article Effects of the Trace Amine Associated Receptor 1 Agonist RO5263397 on Abuse-Related Behavioral Indices of Methamphetamine in Rats Li Jing, PhD; Yanan Zhang, PhD; Jun-Xu Li, PhD Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY (Drs Jing and Li); Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China (Dr Jing); Research Triangle Institute, Research Triangle Park, NC (Dr Zhang). Correspondence: Jun-Xu Li, PhD, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY ([email protected]). Abstract Background: Methamphetamine is a major drug of abuse with no effective pharmacotherapy available. Trace amine associated receptor 1 is implicated in cocaine addiction and represents a potential therapeutic target. However, the effects of trace amine associated receptor 1 agonists on addiction-related behavioral effects of methamphetamine are unknown. Methods: This study examined the effects of a trace amine associated receptor 1 agonist RO5263397 on methamphetamine- induced behavioral sensitization, methamphetamine self-administration, cue- and methamphetamine-induced reinstatement of drug seeking, and cue-induced reinstatement of sucrose-seeking behaviors in rats. Male Sprague-Dawley rats were used to examine the effects of methamphetamine alone and in combination with the trace amine associated receptor 1 agonist RO5263397 (3.2–10 mg/kg). Results: RO5263397 dose-dependently attenuated the expression of behavioral sensitization to methamphetamine, reduced methamphetamine self-administration, and decreased both cue- and a priming dose of methamphetamine-induced reinstatement of drug-seeking behaviors. -
Tyramine and Amyloid Beta 42: a Toxic Synergy
biomedicines Article Tyramine and Amyloid Beta 42: A Toxic Synergy Sudip Dhakal and Ian Macreadie * School of Science, RMIT University, Bundoora, VIC 3083, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-3-9925-6627 Received: 5 May 2020; Accepted: 27 May 2020; Published: 30 May 2020 Abstract: Implicated in various diseases including Parkinson’s disease, Huntington’s disease, migraines, schizophrenia and increased blood pressure, tyramine plays a crucial role as a neurotransmitter in the synaptic cleft by reducing serotonergic and dopaminergic signaling through a trace amine-associated receptor (TAAR1). There appear to be no studies investigating a connection of tyramine to Alzheimer’s disease. This study aimed to examine whether tyramine could be involved in AD pathology by using Saccharomyces cerevisiae expressing Aβ42. S. cerevisiae cells producing native Aβ42 were treated with different concentrations of tyramine, and the production of reactive oxygen species (ROS) was evaluated using flow cytometric cell analysis. There was dose-dependent ROS generation in wild-type yeast cells with tyramine. In yeast producing Aβ42, ROS levels generated were significantly higher than in controls, suggesting a synergistic toxicity of Aβ42 and tyramine. The addition of exogenous reduced glutathione (GSH) was found to rescue the cells with increased ROS, indicating depletion of intracellular GSH due to tyramine and Aβ42. Additionally, tyramine inhibited the respiratory growth of yeast cells producing GFP-Aβ42, while there was no growth inhibition when cells were producing GFP. Tyramine was also demonstrated to cause increased mitochondrial DNA damage, resulting in the formation of petite mutants that lack respiratory function. -
Convergent Pharmacological Mechanisms in Impulsivity And
British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction. -
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Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord Elizabeth A. Gozal, Emory University Brannan E. O'Neill, Emory University Michael A. Sawchuk, Emory University Hong Zhu, Emory University Mallika Halder, Emory University Chou Ching-Chieh , Emory University Shawn Hochman, Emory University Journal Title: Frontiers in Neural Circuits Volume: Volume 8 Publisher: Frontiers | 2014-11-07, Pages 134-134 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.3389/fncir.2014.00134 Permanent URL: https://pid.emory.edu/ark:/25593/mr95r Final published version: http://dx.doi.org/10.3389/fncir.2014.00134 Copyright information: © 2014 Gozal, O'Neill, Sawchuk, Zhu, Halder, Chou and Hochman. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution of derivative works, making multiple copies, distribution, public display, and publicly performance, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact. Accessed September 27, 2021 11:18 AM EDT ORIGINAL RESEARCH ARTICLE published: 07 November 2014 NEURAL CIRCUITS doi: 10.3389/fncir.2014.00134 Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord Elizabeth A. Gozal , Brannan E. O’Neill , Michael A. Sawchuk , Hong Zhu , Mallika Halder , Ching-Chieh Chou and Shawn Hochman* Physiology Department, Emory University, Atlanta, GA, USA Edited by: The trace amines (TAs), tryptamine, tyramine, and β-phenylethylamine, are synthesized Brian R. -
Autonomic Nervous System Activity Changes in Patients with Hypertension and Overweight: Role and Therapeutic Implications Paul Valensi*
Valensi Cardiovasc Diabetol (2021) 20:170 https://doi.org/10.1186/s12933-021-01356-w Cardiovascular Diabetology REVIEW Open Access Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications Paul Valensi* Abstract The incidence and prevalence of hypertension is increasing worldwide, with approximately 1.13 billion of people currently afected by the disease, often in association with other diseases such as diabetes mellitus, chronic kidney disease, dyslipidemia/hypercholesterolemia, and obesity. The autonomic nervous system has been implicated in the pathophysiology of hypertension, and treatments targeting the sympathetic nervous system (SNS), a key component of the autonomic nervous system, have been developed; however, current recommendations provide little guid‑ ance on their use. This review discusses the etiology of hypertension, and more specifcally the role of the SNS in the pathophysiology of hypertension and its associated disorders. In addition, the efects of current antihypertensive management strategies, including pharmacotherapies, on the SNS are examined, with a focus on imidazoline recep‑ tor agonists. Keywords: Autonomic nervous system, Hypertension, Obesity, Type 2 diabetes, Selective imidazoline receptor agonists Introduction 6]. Te prevalence of hypertension is higher in low- and Hypertension is one of the leading causes of premature middle-income countries [5] and increases with age [1]. death worldwide with 1.13 billion people having hyper- Te autonomic nervous system has been implicated tension. It is associated with an increased risk of cardio- in the pathophysiology of hypertension [7, 8] and treat- vascular diseases (CVD; e.g., stroke, angina, myocardial ments targeting the sympathetic nervous system (SNS) infarction, heart failure, peripheral artery disease, and have been developed [9, 10] although largely forgotten or abdominal aortic aneurysm) as well as end-stage renal ruled out in international recommendations [1, 2]. -
Download Product Insert (PDF)
PRODUCT INFORMATION Guanfacine (hydrochloride) Item No. 22907 CAS Registry No.: 29110-48-3 Formal Name: N-(aminoiminomethyl)-2,6-dichloro- Cl H benzeneacetamide, monohydrochloride N NH2 MF: C9H9Cl2N3O • HCl FW: 282.6 O NH Purity: ≥98% Supplied as: A crystalline solid Cl • HCl Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Guanfacine (hydrochloride) is supplied as a crystalline solid. A stock solution may be made by dissolving the guanfacine (hydrochloride) in the solvent of choice. Guanfacine (hydrochloride) is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of guanfacine (hydrochloride) in ethanol is approximately 25 mg/ml and approximately 30 mg/ml in DMSO and DMF. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of guanfacine (hydrochloride) can be prepared by directly dissolving the crystalline solid in aqueous buffers. The solubility of guanfacine (hydrochloride) in PBS, pH 7.2, is approximately 10 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description Guanfacine is an α2-adrenergic receptor (α2-AR) agonist with Ki values of 93, 1,380, and 3,890 nM for α2A-, 1 α2B-, and α2C-ARs, respectively, in a radioligand binding assay. It has EC50 values of 52, 288, and 602 nM for 35 α2A-, α2B-, and α2C-ARs, respectively, for stimulated [ S]GTPγS binding. -
Food Sources and Biomolecular Targets of Tyramine
Special Article Food sources and biomolecular targets of tyramine Gaby Andersen, Patrick Marcinek, Nicole Sulzinger, Peter Schieberle, and Dietmar Krautwurst Tyramine is a biogenic trace amine that is generated via the decarboxylation of the amino acid tyrosine. At pico- to nanomolar concentrations, it can influence a multi- tude of physiological mechanisms, exhibiting neuromodulatory properties as well as cardiovascular and immunological effects. In humans, the diet is the primary Downloaded from https://academic.oup.com/nutritionreviews/article/77/2/107/5084469 by guest on 24 September 2021 source of physiologically relevant tyramine concentrations, which are influenced by a large number of intrinsic and extrinsic factors. Among these factors are the avail- ability of tyrosine in food, the presence of tyramine-producing bacteria, the environ- mental pH, and the salt content of food. The process of fermentation provides a particularly good source of tyramine in human nutrition. Here, the potential impact of dietary tyramine on human health was assessed by compiling quantitative data on the tyramine content in a variety of foods and then conducting a brief review of the literature on the physiological, cellular, and systemic effects of tyramine. Together, the data sets presented here may allow both the assessment of tyramine concentrations in food and the extrapolation of these concentrations to gauge the physiological and systemic effects in the context of human nutrition. INTRODUCTION presence of tyramine in a variety of foods, (2) the post- prandial physiological and adverse effects of tyramine, Tyramine is a biogenic amine generated via the decar- and (3) the biomolecular targets of tyramine. It is not boxylation of the amino acid tyrosine in animals, plants, intended to be a systematic or comprehensive review of and microorganisms. -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.