DOCSLIB.ORG

A Complete Assessment of Dopamine Receptor- Ligand Interactions Through Computational Methods

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Complete Assessment of Dopamine Receptor- Ligand Interactions Through Computational Methods molecules Article A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods Beatriz Bueschbell 1 , Carlos A. V. Barreto 2 , António J. Preto 2, Anke C. Schiedel 1 and Irina S. Moreira 2,3,* 1 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, D-53121 Bonn, Germany; [email protected] (B.B.); [email protected] (A.C.S.) 2 Center for Neuroscience and Cell Biology, UC- Biotech Parque Tecnológico de Cantanhede, Núcleo 04, Lote B, 3060-197 Cantanhede, Portugal; [email protected] (C.A.V.B.); [email protected] (A.J.P.) 3 Institute for Interdisciplinary Research, University of Coimbra, 3004-531 Coimbra, Portugal * Correspondence: [email protected]; Tel.: +351-231-249-730 Received: 5 February 2019; Accepted: 23 March 2019; Published: 27 March 2019 Abstract: Background: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like). Fifteen structurally diverse ligands were docked. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for selective binding to DR subtypes. Results: Residues of the aromatic microdomain were shown to be responsible for the majority of ligand interactions established to all DRs. Hydrophobic contacts involved a huge network of conserved and non-conserved residues between three transmembrane domains (TMs), TM2-TM3-TM7. Hydrogen bonds were mostly mediated by the serine microdomain. TM1 and TM2 residues were main contributors for the coupling of large ligands. Some amino acid groups form electrostatic interactions of particular importance for D1R-like selective ligands binding. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands. Keywords: dopamine receptors; molecular docking; molecular dynamics; receptor-ligand interactions 1. Introduction 1.1. Dopamine Receptors The dopaminergic system has been intensively studied over the past 75 years due to the (patho)physiological role in modulating cognitive and motor behaviour [1,2]. The importance of dopamine has dramatically emerged from being just an intermediate in the formation of noradrenaline to having a celebrity status as the most important mammalian neurotransmitter [3]. Dopamine binds to five distinct dopamine receptors (DRs; D1–5 Receptor), grouped into two classes —D1-like and D2-like receptors— that differ in their physiological effects and signal transduction. The D1-like receptors, D1R and D5R, are principally coupled to Gs proteins and enhance the activity of adenylyl-cyclase, whereas D2-like receptors, D2–4R, are primarily coupled to inhibitory Gi proteins and suppress the activity of adenylyl cyclases [1,4]. The DRs belong to the G Protein-Coupled Receptor family (GPCRs), the largest and most diverse protein family in humans with approximately 800 members [5,6]. Molecules 2019, 24, 1196; doi:10.3390/molecules24071196 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 26 adenylyl-cyclase, whereas D2-like receptors, D2–4R, are primarily coupled to inhibitory Gi proteins andMolecules suppress2019, 24 ,the 1196 activity of adenylyl cyclases [1,4]. The DRs belong to the G Protein-Coupled2 of 26 Receptor family (GPCRs), the largest and most diverse protein family in humans with approximately 800 members [5,6]. GPCRs share a conserved overall fold of seven transmembrane helices (TMs) GPCRs share a conserved overall fold of seven transmembrane helices (TMs) linked by three linked by three intracellular loops (ICLs) and three extracellular loops (ECLs). Around 30–40% of all intracellular loops (ICLs) and three extracellular loops (ECLs). Around 30–40% of all available available pharmacotherapeutics target this protein family [7]. pharmacotherapeutics target this protein family [7]. Many severe neuropsychiatric and neurodegenerative disorders such as Tourette’s syndrome, Many severe neuropsychiatric and neurodegenerative disorders such as Tourette’s syndrome, schizophrenia, Parkinson’s disease and Huntington’s disease are believed to occur as a result of schizophrenia, Parkinson’s disease and Huntington’s disease are believed to occur as a result imbalances and alterations in dopamine signaling [8–10]. Moreover, also a wide array of psychiatric of imbalances and alterations in dopamine signaling [8–10]. Moreover, also a wide array of disorders such as hallucinations, paranoia, bipolar disorder, gambling, alcoholism, mania, psychiatric disorders such as hallucinations, paranoia, bipolar disorder, gambling, alcoholism, mania, depression, eating disorders, movement and hyperactivity disorders are linked to malfunctioning depression, eating disorders, movement and hyperactivity disorders are linked to malfunctioning dopaminergic transmission [3,11–13]. The discovery of chlorpromazine, the first antipsychotic drug, dopaminergic transmission [3,11–13]. The discovery of chlorpromazine, the first antipsychotic in the 1950s, was the hallmark of the development of a collection of antipsychotics [14] which were drug, in the 1950s, was the hallmark of the development of a collection of antipsychotics [14] later reported to commonly bind to the D2R subtype (with different affinity) [4,11]. The “first- which were later reported to commonly bind to the D2R subtype (with different affinity) [4,11]. generation/classical” antipsychotics came along with significant motor side effects such as tardive The “first-generation/classical” antipsychotics came along with significant motor side effects such dyskinesia, extrapyramidal symptoms and related conditions. These problems were not eliminated as tardive dyskinesia, extrapyramidal symptoms and related conditions. These problems were not in “second-generation/atypical” antipsychotics, and others such as weight gain and the “metabolic eliminated in “second-generation/atypical” antipsychotics, and others such as weight gain and the syndrome” also appeared [11,15–17]. It was then later discovered that these multiple clinical and “metabolic syndrome” also appeared [11,15–17]. It was then later discovered that these multiple clinical adverse effects of several antipsychotics depended on the combination of occupied receptors from and adverse effects of several antipsychotics depended on the combination of occupied receptors from other systems such as cholinergic, histaminergic and serotoninergic receptors (but always including other systems such as cholinergic, histaminergic and serotoninergic receptors (but always including the the D2R) resulting in non-selective profiles and therefore in an insufficient explanation of the D R) resulting in non-selective profiles and therefore in an insufficient explanation of the mechanism mechanism2 of action [11,15]. Until today, no drug has yet been identified with antipsychotic action of action [11,15]. Until today, no drug has yet been identified with antipsychotic action without without a significant affinity for the D2R [15]. However, antipsychotics remain a necessary first-line a significant affinity for the D R[15]. However, antipsychotics remain a necessary first-line treatment treatment for the management2 of a variety of the already mentioned psychiatric disorders (Figure 1). for the management of a variety of the already mentioned psychiatric disorders (Figure1). In fact, In fact, it is difficult to directly target one of these diseases with one specific antipsychotic, since there it is difficult to directly target one of these diseases with one specific antipsychotic, since there are are also numerous cases of non-responding patients to first-line or any antipsychotic treatment or also numerous cases of non-responding patients to first-line or any antipsychotic treatment or which which become resistant to treatment over time [11,18]. become resistant to treatment over time [11,18]. Figure 1. Examples for first-line treatments of neurological diseases and selective dopamine receptor Figure 1. Examples for first-line treatments of neurological diseases and selective dopamine receptor ligands. Drugs are classified in typical and atypical antipsychotics [19]. The targets of the selective ligands.ligands haloperidole,Drugs are classified 7-OH-DPAT, in typical SCH23390 and atypical and SKF38393 antipsychotics were colored [19]. The in blue. targets of the selective ligands haloperidole, 7-OH-DPAT, SCH23390 and SKF38393 were colored in blue. The search for DR subtype selective (foremost D2R-selective) therapeutics is an ongoing field of research [15] as current drugs have D2R/D3R-affinity or affinity for all DRs [19,20]. It has been proposed Molecules 2019, 24, 1196 3 of 26 that substituted 4-phenylpiperazine compounds distinguish between D3R and D2R selectivity [21,22]. In addition, the aminotetraline derivative 7-OH-DPAT was identified as a selective D3R agonist [23,24], whereas it was shown that most D4R available therapeutics are not selective [22], with only one exception, haloperidole [25]
Load more

Recommended publications
  • Interview with Pierre Pichot
    PSYCHOPHARMACOLOGY AND THE HISTORY OF PSYCHIATRY PIERRE PICHOT Could we begin with your recollections of the 1955 Paris meeting, which was effectively the first world wide meeting on chlorpromazine. The meeting was organised in Paris by Jean Delay. It was supported by Specia, the pharmaceutical firm which had produced chlorpromazine, which was a branch of the Rhone Poulenc Group. For the first time people engaged in what was called psychopharmacology came together. They came from many countries, including the United States. The efficacy of the drug and the mechanism of action were discussed. However, at that time the biochemistry of the brain, as it exists now, was unknown. It was only at the beginning of the 60s, that we began to speak of the role of the neurotransmitters in the action of both neuroleptic drugs and antidepressants and of their potential abnormalities in the disease process. So in practice 1955 was only a meeting on therapy with chlorpromazine. I have always been very much impressed by the fact that chlorpromazine, which had been introduced only 3 years before, was already used all over the world. Theoretical ideas take usually a very long time to travel from one country to another, and sometimes they never make it. I quote always, the case of Karl Jaspers’ General Psychopathology, which is considered in the German speaking world as one of the basic books of psychiatry. This was published in 1913 but appeared in English translation only in 1963, 50 years later and, even then, a paper published in the American Journal of Psychiatry wrote ingenuously that, until this publication, many psychiatrists in the United States had not realised that Jaspers was not only a philosopher, but also a psychiatrist.
    [Show full text]
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • 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.
    [Show full text]
  • Biased Allosteric Regulation of the Prostaglandin F2α Receptor: From
    Biased Allosteric Regulation of the Prostaglandin F2 Receptor: From Small Molecules to Large Receptor Complexes By Eugénie Goupil Department of Pharmacology and Therapeutics McGill University, Montréal, Canada November, 2012 A thesis submitted to McGill in partial fulfillment of the requirements of the degree of Doctor of philosophy Copyright ©Eugénie Goupil, 2012 ''In theory, there is no difference between theory and practice. In practice, there is.'' -Lawrence Peter ''Yogi'' Berra ii Abstract G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors, and thus some of the most important targets for drug discovery. By binding to the orthosteric site where endogenous ligands bind, agonists and antagonists differentially modulate signals sent downstream from these receptors. New evidence suggests that GPCRs possess topographically distinct or allosteric binding sites, which may differentially modulate agonist- and antagonist-mediated responses to selectively affect distinct signalling pathways coupled to the same receptor. These sites may either positively or negatively regulate receptor activity, depending on the pathway in question, and thus can act as biased ligands, leading to functional selectivity (or ligand-directed signalling). Another way of allosterically regulating GPCR signalling is through receptor oligomerization, which has recently emerged as a common mechanism for regulating receptor function. The GPCR for prostaglandin F2 FP, is implicated in many important physiological responses, such as parturition, smooth muscle cell contraction and blood pressure regulation. Therefore, evaluating the potential use of allosteric modulators of FP to fine-tune PGF2-mediated signals, as well as generating a better understanding of its putative oligomerization partners would be of significant pharmacological and clinical interest.
    [Show full text]
  • Assessing Neurotoxicity of Drugs of Abuse
    National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Assessing Neurotoxicity of Drugs of Abuse 136 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Assessing Neurotoxicity of Drugs of Abuse Editor: Lynda Erinoff, Ph.D. NIDA Research Monograph 136 1993 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT This monograph is based on the papers and discussions from a technical review on “Assessing Neurotoxicity of Drugs of Abuse” held on May 20-21, 1991, in Bethesda, MD. The technical review was sponsored by the National Institute on Drug Abuse (NIDA). COPYRIGHT STATUS NIDA 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 material 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. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company.
    [Show full text]
  • Steven, Stacy (2012) the Pharmacology of the 5-HT2A Receptor and the Difficulty Surrounding Single Taret Models
    Steven, Stacy (2012) The pharmacology of the 5-HT2A receptor and the difficulty surrounding single taret models. MSc(R) thesis. http://theses.gla.ac.uk/3636/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] The pharmacology of the 5-HT2A receptor and the difficulty surrounding functional studies with single target models A thesis presented for the degree of Master of Science by research Stacy Steven April 2012 Treatment of many disorders can be frequently problematic due to the relatively non selective nature of many drugs available on the market. Symptoms can be complex and expansive, often leading to symptoms representing other disorders in addition to the primary reason for treatment. In particular mental health disorders fall prey to this situation. Targeting treatment can be difficult due to the implication of receptors in more than one disorder, and more than one receptor in a single disorder. In the instance of GPCRs, receptors such as the serotonin receptors (and in particular the 5-HT2A for the interest of this research) belong to a large family of receptors, the GPCR Class A super family.
    [Show full text]
  • Characterization of Multiple Sites of Action of Ibogaine
    ——Chapter 6—— CHARACTERIZATION OF MULTIPLE SITES OF ACTION OF IBOGAINE Henry Sershen, Audrey Hashim, And Abel Lajtha Nathan Kline Institute Orangeburg, New York 10962 I. Introduction.................................................................................................................. II. Issues Related to Ibogaine in the Treatment of Drug Dependence............................. A. Dopamine as a Primary Site of Drug-Mediated Responses .................................. B. Ibogaine or Its Metabolite and Acute versus Long-Term Effect........................... C. Single or Multiple Sites of Action of Ibogaine ..................................................... III. Effect of Ibogaine on Drug-Induced Behavior............................................................ IV. Binding Site Activity ................................................................................................... A. Relevant Site of Action.......................................................................................... V. Functional Activity ...................................................................................................... VI. Stimulant Drug Actions/Behaviors.............................................................................. VII. Current Non-Ibogaine Drug Treatment Protocols ....................................................... VIII. Conclusions.................................................................................................................. References...................................................................................................................
    [Show full text]
  • 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).
    [Show full text]
  • Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation
    www.sciencemag.org/cgi/content/full/327/5963/348/DC1 Supporting Online Material for Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation Jason Rihel,* David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, Stephen J. Haggarty, David Kokel, Lee L. Rubin, Randall T. Peterson, Alexander F. Schier* *To whom correspondence should be addressed. E-mail: [email protected] (A.F.S.); [email protected] (J.R.) Published 15 January 2010, Science 327, 348 (2010) DOI: 10.1126/science.1183090 This PDF file includes: Materials and Methods SOM Text Figs. S1 to S18 Table S1 References Supporting Online Material Table of Contents Materials and Methods, pages 2-4 Supplemental Text 1-7, pages 5-10 Text 1. Psychotropic Drug Discovery, page 5 Text 2. Dose, pages 5-6 Text 3. Therapeutic Classes of Drugs Induce Correlated Behaviors, page 6 Text 4. Polypharmacology, pages 6-7 Text 5. Pharmacological Conservation, pages 7-9 Text 6. Non-overlapping Regulation of Rest/Wake States, page 9 Text 7. High Throughput Behavioral Screening in Practice, page 10 Supplemental Figure Legends, pages 11-14 Figure S1. Expanded hierarchical clustering analysis, pages 15-18 Figure S2. Hierarchical and k-means clustering yield similar cluster architectures, page 19 Figure S3. Expanded k-means clustergram, pages 20-23 Figure S4. Behavioral fingerprints are stable across a range of doses, page 24 Figure S5. Compounds that share biological targets have highly correlated behavioral fingerprints, page 25 Figure S6. Examples of compounds that share biological targets and/or structural similarity that give similar behavioral profiles, page 26 Figure S7.
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Accelerated Resensitization of the D 1 Dopamine Receptor-Mediated
    The Journal of Neuroscience, October 1994, 74(10): 6260-6266 Accelerated Resensitization of the D 1 Dopamine Receptor-mediated Response in Cultured Cortical and Striatal Neurons from the Rat: Respective Role of CY1 -Adrenergic and /U-methybaspartate Receptors Fabrice Trovero, Philippe Marin, Jean-PO1 Tassin, JoQl Premont, and Jacques Glowinski INSERM U 114, Chaire de Neuropharmacologie, College de France, 75231 Paris Cedex, France As previously shown in vivo, noradrenergic and glutama- cortex. In the rat, bilateral electrolytic lesions of the mesence- tergic neurons can regulate the denervation supersensitivity phalic ventral tegmental area induce a complex and permanent of Dl dopaminergic (DA) receptors in the rat prefrontal cor- behavioral syndrome characterized by a locomotor hyperactiv- tex and striatum respectively. Therefore, the effects of meth- ity and the incapacity of the animal to focalize its attention (Le oxamine (an al-adrenergic agonist) and glutamate on the Moal et al., 1969). Some of the behavioral deficits observed in resensitization of Dl DA receptors were investigated in cul- the lesioned animals, particularly the locomotor hyperactivity, tured cortical and striatal neurons from the embryonic rat. have been attributed for a large part to the selective destruction In the presence of sulpiride and propranolol, DA stimulated of the cortical dopaminergic (DA) innervation (Tassin et al., the Dl DA receptor-mediated conversion of 3H-adenine into 1978). This locomotor hyperactivity was markedly reduced in 3H-cAMP in both intact cortical and striatal cells and these rats with 6-hydroxydopamine (6-OHDA) lesions,which destroy responses were markedly desensitized in cells preexposed not only the ascendingDA neurons but also the ascendingnor- for 15 min to DA (50 AM).
    [Show full text]
  • Testosterone for Women...And Men
    Testosterone for Women...and Men Date: 05/08/2006 Posted By: Jon Barron Every now and then I get a break in putting together a newsletter. I get to steal the entire newsletter from myself. In this case, I was able to take most of the material for this newsletter from the formulation information I put together for my new upgraded Women's Formula that Baseline Nutritionals released this month. And while this newsletter definitely serves as an introduction to that new formula, it more importantly provides an excuse for exploring a crucial topic for both men and women -- the value of maintaining an optimum testosterone balance. However, before we get into the specifics of both the men's and women's formulas, let's explore what testosterone does in the body -- and why it's so important for both men and women. The 30,000 Mile Tune-Up: Hormonal Changes As men and women enter their 30's, profound changes begin to take place in their bodies. If not addressed (that's the 30,000 mile tune-up thing), these changes can lead to, among other things: • Decreased energy and zest for life • Loss of muscle tone and increased fat • Circulatory problems and decreased libido But it doesn't have to be this way. Let me explain. Hormonal Imbalance Hormones are the body's chemical messenger system. They tell the various cells of the body what to do - - and when to do it -- by attaching to specific receptor sites on individual cells. Problems occur when the various hormones get out of balance.
    [Show full text]