Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines
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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. -
4695389.Pdf (3.200Mb)
Non-classical amine recognition evolved in a large clade of olfactory receptors The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Li, Qian, Yaw Tachie-Baffour, Zhikai Liu, Maude W Baldwin, Andrew C Kruse, and Stephen D Liberles. 2015. “Non-classical amine recognition evolved in a large clade of olfactory receptors.” eLife 4 (1): e10441. doi:10.7554/eLife.10441. http://dx.doi.org/10.7554/ eLife.10441. Published Version doi:10.7554/eLife.10441 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993622 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA RESEARCH ARTICLE Non-classical amine recognition evolved in a large clade of olfactory receptors Qian Li1, Yaw Tachie-Baffour1, Zhikai Liu1, Maude W Baldwin2, Andrew C Kruse3, Stephen D Liberles1* 1Department of Cell Biology, Harvard Medical School, Boston, United States; 2Department of Organismic and Evolutionary Biology, Museum of Comparative Zoology, Harvard University, Cambridge, United States; 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States Abstract Biogenic amines are important signaling molecules, and the structural basis for their recognition by G Protein-Coupled Receptors (GPCRs) is well understood. Amines are also potent odors, with some activating olfactory trace amine-associated receptors (TAARs). Here, we report that teleost TAARs evolved a new way to recognize amines in a non-classical orientation. -
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. -
Neurotransmitters-Drugs Andbrain Function.Pdf
Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd. -
Selective Labeling of Serotonin Receptors Byd-[3H]Lysergic Acid
Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 5783-5787, December 1978 Biochemistry Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate (ergots/hallucinogens/tryptamines/norepinephrine/dopamine) PATRICIA M. WHITAKER AND PHILIP SEEMAN* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8 Communicated by Philip Siekevltz, August 18,1978 ABSTRACT Since it was known that d-lysergic acid di- The objective in this present study was to improve the se- ethylamide (LSD) affected catecholaminergic as well as sero- lectivity of [3H]LSD for serotonin receptors, concomitantly toninergic neurons, the objective in this study was to enhance using other drugs to block a-adrenergic and dopamine receptors the selectivity of [3HJISD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of (cf. refs. 36-38). We then compared the potencies of various a combination of 50 nM each of phentolamine (adde to pre- drugs on this selective [3H]LSD binding and compared these clude the binding of [3HJLSD to a-adrenoceptors), apmo ie, data to those for the high-affinity binding of [3H]serotonin and spiperone (added to preclude the binding of [3H[LSD to (39). dopamine receptors), it was found by Scatchard analysis that the total number of 3H sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catechol- METHODS amine-blocking drugs. The IC50 values (concentrations to inhibit Preparation of Membranes. Calf brains were obtained fresh binding by 50%) for various drugs were tested on the binding of [3HLSD in the presence of 50 nM each of apomorphine (A), from the Canada Packers Hunisett plant (Toronto). -
Pharmacology and Toxicology of Amphetamine and Related Designer Drugs
Pharmacology and Toxicology of Amphetamine and Related Designer Drugs U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol Drug Abuse and Mental Health Administration Pharmacology and Toxicology of Amphetamine and Related Designer Drugs Editors: Khursheed Asghar, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Errol De Souza, Ph.D. Addiction Research Center National Institute on Drug Abuse NIDA Research Monograph 94 1989 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 Pharmacology and Toxicology of Amphetamine and Related Designer Drugs ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on pharmacology and toxicology of amphetamine and related designer drugs that took place on August 2 through 4, 1988, in Bethesda, MD. The review meeting was sponsored by the Biomedical Branch, Division of Preclinical Research, and the Addiction Research Center, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other matieral in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. -
Amphetamine Derivatives Interact with Both Plasma Membrane and Secretory Vesicle Biogenic Amine Transporters
'4 0026-895X/93/061227-05503.00/0 Copyright © by The American Society for Pharmacology and Experimental Therapeutics AIl rights of reproduction in any form reserved. MOLECULAR PHARMACOLOGY, 44:1227-1231 Amphetamine Derivatives Interact with Both Plasma Membrane and Secretory Vesicle Biogenic Amine Transporters SHIMON SCHULDINER, SONIA STEINER-MORDOCH, RODRIGO YELIN, STEPHEN C. WALL, and GARY RUDNICK Departmentof Pharmacology,YaleUniversitySchool of Medicine,New Haven,CT 06510 (S.C.W.,G.R.) andAlexanderSilbermanInstituteof Life Sciences,TheHebrew University,GivatRam, Jerusalem,Israel (S.S.,S.S.-M., R.Y.) ReceivedJune 7, 1993; Accepted September 16, 1993 SUMMARY The interaction of fenfluramine, 3,4-methylenedioxymethamphe- porter, fenfiuramine inhibited serotonin transport and dissipated tamine (MDMA), and p-chloroamphetamine (PCA) with the plate- the transmembrane pH difference (ApH) that drives amine up- let plasma membrane serotonin transporter and the vesicular take. The use of [3H]reserpine-binding measurements to deter- amine transporter were studied using both transport and binding mine drug interaction with the vesicular amine transporter al- measurements. Fenfluramine is apparently a substrate for the lowed assessment of the relative ability of MDMA, PCA, and plasma membrane transporter, and consequently inhibits both fenfluramine to bind to the substrate site of the vesicular trans- serotonin transport and imipramine binding. Moreover, fenflura- porter. These measurements permit a distinction between inhi- mine exchanges with internal [3H]serotonin in a plasma mem- bition of vesicular serotonin transport by directly blocking vesic- brane transporter-mediated reaction that requires NaCI and is ular amine transport and by dissipating ApH. The results indicate blocked by imipramine. These properties are similar to those of that MDMA and fenfluramine inhibit by both mechanisms but MDMA and PCA as previously described. -
Ring-Substituted Amphetamine Interactions with Neurotransmitter Receptor Binding Sites in Human Cortex
208 NeuroscienceLetters, 95 (1988) 208-212 Elsevier Scientific Publishers Ireland Ltd. NSL O5736 Ring-substituted amphetamine interactions with neurotransmitter receptor binding sites in human cortex Pamela A. Pierce and Stephen J. Peroutka Deparmentsof Neurologyand Pharmacology, Stanford University Medical Center, StanJbrd,CA 94305 (U.S.A.) (Received 31 May 1988; Revised version received 11 August 1988; Accepted 12 August 1988) Key words.' Ring-substituted amphetamine; (_+)-3,4-Methylenedioxyamphetamine; ( +_)-3,4-Methylene- dioxyethamphetamine; (_+)-3,4-Methylenedioxymethamphetamine; Ecstasy; 4-Bromo-2,5- dimethoxyphenylisopropylamine binding site; Human cortical receptor The binding affinities of 3 ring-substituted amphetamine compounds were determined at 9 neurotrans- mitter binding sites in human cortex. (_+)-3,4-Methylenedioxyamphetamine (MDAk (_+)-3,4-methylene- dioxyethamphetamine (MDE), and (_+)-3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') all display highest affinity (approximately 1 /tM) for the recently identified 'DOB binding site' labeled by ['TBr]R(-)4-bromo-2,5-dimethoxyphenylisopropylamine ([77Br]R(-)DOB). MDA displays moderate affinity (4-5/iM) for the 5-hydroxytryptaminetA (5-HTr^), 5-HT_D,and =,-adrenergic sites in human cor- tex. MDE and MDMA display lower affinity or are inactive at all other sites tested in the present study. These observations are discussed in relation to the novel psychoactive effects of the ring-substituted amphetamines. A series of ring-substituted amphetamine derivatives exist which are structurally related to both amphetamines and hallucinogens. However, drugs such as (+)-3,4- methylenedioxyamphetamine (MDA), (_+)-3,4-methylenedioxyethamphetamine (MDE), and (+)-3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') ap- pear to produce unique psychoactive effects which are distinct from the effects of both amphetamines and hallucinogens [13, 15]. -
Discovery of Novel Imidazolines and Imidazoles As Selective TAAR1
Discovery of Novel Imidazolines and Imidazoles as Selective TAAR1 Partial Agonists for the Treatment of Psychiatric Disorders Giuseppe Cecere, pRED, Discovery Chemistry F. Hoffmann-La Roche AG, Basel, Switzerland Biological Rationale Trace amines are known for four decades Trace Amines - phenylethylamine p- tyramine p- octopamine tryptamine (PEA) Biogenic Amines dopamine norepinephrine serotonin ( DA) (NE) (5-HT) • Structurally related to classical biogenic amine neurotransmitters (DA, NE, 5-HT) • Co-localised & released with biogenic amines in same cells and vesicles • Low concentrations in CNS, rapidly catabolized by monoamine oxidase (MAO) • Dysregulation linked to psychiatric disorders such as schizophrenia & 2 depression Trace Amines Metabolism 3 Biological Rationale Trace Amine-Associated Receptors (TAARs) p-Tyramine extracellular TAAR1 Discrete family of GPCR’s Subtypes TAAR1-TAAR9 known intracellular Gs Structural similarity with the rhodopsin and adrenergic receptor superfamily adenylate Activation of the TAAR1 cyclase receptor leads to cAMP elevation of intracellular cAMP levels • First discovered in 2001 (Borowsky & Bunzow); characterised and classified at Roche in 2004 • Trace amines are endogenous ligands of TAAR1 • TAAR1 is expressed throughout the limbic and monoaminergic system in the brain Borowsky, B. et al., PNAS 2001, 98, 8966; Bunzow, J. R. et al., Mol. Pharmacol. 2001, 60, 1181. Lindemann L, Hoener MC, Trends Pharmacol Sci 2005, 26, 274. 4 Biological Rationale Electrical activity of dopaminergic neurons + p-tyramine -
Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives Strucrure-Acfivity RELA TIONSHIPS Ma
Biochemieal PhannaeoloR)'. Vol. 54. pp. 1361-1369, 1997. ISSN 0006-2952/97/$17.00 + 0.00 © 1997 Elsevier Scienee Ine. Al! rights reserved. PIl SOOO6-2952(97)00405·X ELSEVIER Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives STRUcruRE-ACfIVITY RELA TIONSHIPS Ma. Cecilia Scorza,* Cecilia Carrau,* Rodolfo Silveira,* GemId Zapata,Torres,t Bruce K. Casselst and Miguel Reyes,Parada*t *DIVISIÓNBIOLOGíACELULAR,INSTITUTODEINVESTIGACIONESBIOLÓGICASCLEMENTeEsTABlE, CP 11600, MONTEVIOEO,URUGUAY;ANDtDEPARTAMENTODEQUíMICA, FACULTADDECIENCIAS,UNIVERSIDADDECHILE, SANTIAGO,CHILE ABSTRACT. The monoamine oxidase (MAO) inhibitory propenies of a series of amphetamine derivatives with difTerent substituents at or around rhe para position of the aromaric ring were evaluateJ. i¡, in viero stuJies in which a crude rar brain mirochllndrial suspension was used as rhe source of MAO, several compounds showed a srrong (ICS0 in rhe submicromolar range), selecrive, reversible, time-independenr, and concenrrarion-related inhibition of MAO-A. After i.p. injection, the compounds induced an inerease of serotonin and a decrease of j-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confinning rhe in virro results. The analysis of structure-activity relationships indicates rhat: molecules with amphetamine-Iike structure and different substitutions nn the aromaric ring are potentially MAO-A inhibitors; substituents at different positions of the aromatic ring moditY the porency but have litde inf1uence "n the selectiviry; substituents at rhe para position sllch as ,lmino, alkoxyl. halogens. or alkylthio produce a significant increase in rhe acrivity; the para-substituent musr be an e1ectron Jonor; hulky ~roups next to rhe para subsriruent Icad ro a Jecrease in the actÍ\'ityi ,ubstiruents loearcd ar posirions more Jistant ,m rhe aromaric ring havc less intluence anJ, even when the subsriruent is '1 halogen (CI, Br), an increase in rhe acrivity "f rhe cllmpound is llbtained. -
Differential Regulation of Mecp2 Phosphorylation in the CNS by Dopamine and Serotonin
Neuropsychopharmacology (2012) 37, 321–337 & 2012 American College of Neuropsychopharmacology. All rights reserved 0893-133X/12 www.neuropsychopharmacology.org Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin 1 1 2 1,2,3,4 ,1 Ashley N Hutchinson , Jie V Deng , Dipendra K Aryal , William C Wetsel and Anne E West* 1 2 Department of Neurobiology, Duke University Medical Center, Durham, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke 3 University Medical Center, Durham, NC, USA; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, 4 Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D1-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D2-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. -
Characterization of Dopaminergic System in the Striatum of Young Adult Park2-/- Knockout Rats
www.nature.com/scientificreports OPEN Characterization of Dopaminergic System in the Striatum of Young Adult Park2−/− Knockout Rats Received: 27 June 2016 Jickssa M. Gemechu1,2, Akhil Sharma1, Dongyue Yu1,3, Yuran Xie1,4, Olivia M. Merkel 1,5 & Accepted: 20 November 2017 Anna Moszczynska 1 Published: xx xx xxxx Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our fndings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling.