DOCSLIB.ORG

Cholinergic Receptor Subtypes and Their Role in Cognition, Emotion, and Vigilance Control: an Overview of Preclinical and Clinical Findings

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cholinergic Receptor Subtypes and Their Role in Cognition, Emotion, and Vigilance Control: an Overview of Preclinical and Clinical Findings Psychopharmacology (2011) 215:205–229 DOI 10.1007/s00213-010-2153-8 REVIEW Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings Susanne Graef & Peter Schönknecht & Osama Sabri & Ulrich Hegerl Received: 15 June 2010 /Accepted: 15 December 2010 /Published online: 8 January 2011 # Springer-Verlag 2011 Abstract memory, whereas the α4β2* subtype has been linked to Rationale The cholinergic system has long been linked to tests of attention. Both muscarinic and nicotinic cholinergic cognitive processes. Two main classes of acetylcholine mechanisms play a role in modulating brain electrical (ACh) receptors exist in the human brain, namely musca- activity. Nicotinic receptors have been strongly associated rinic and nicotinic receptors, of which several subtypes with the modulation of depression and anxiety. occur. Conclusions Cholinergic receptor manipulations have an Objectives This review seeks to provide an overview of effect on cognition, emotion, and brain electrical activity as previous findings on the influence of cholinergic receptor measured by EEG. Changes in cognition can result from direct manipulations on cognition in animals and humans, with cholinergic receptor manipulation or from cholinergically particular emphasis on the role of selected cholinergic induced changes in vigilance or affective state. receptor subtypes. Furthermore, the involvement of these receptor subtypes in the regulation of emotion and brain Keywords nAChR . Nicotinic receptor . Acetylcholine electrical activity as measured by electroencephalography receptor . Vigilance . Cognition . Working memory . (EEG) shall be addressed since these domains are considered Attention . Depression . Anxiety to be important modulators of cognitive functioning. Results In regard to cognition, the muscarinic receptor Abbreviations subtypes have been implicated mainly in memory func- 5-CSRT Five-choice serial reaction time tions, but have also been linked to attentional processes. ACh Acetylcholine The nicotinic α7 receptor subtype is involved in working CPT Continuous performance task EEG Electroencephalography FDG Fluoro-2-deoxy-D-glucose The asterisk used in the receptor nomenclature indicates that the HVS High-voltage spindle receptor complex may contain additional subunits. : : mAChR Muscarinic acetylcholine receptor S. Graef (*) P. Schönknecht U. Hegerl MPTP Methylphenyltetrahydropyridin Department of Psychiatry, University of Leipzig, nAChR Nicotinic acetylcholine receptor Semmelweisstr. 10, 04103 Leipzig, Germany PET Positron emission tomography e-mail: [email protected] O. Sabri Department of Nuclear Medicine, University of Leipzig, Liebigstr. 18, Introduction 04103 Leipzig, Germany The observation that cholinergic markers in the cerebral S. Graef cortex such as choline acetyltransferase or acetylcholines- Max Planck Institute for Human Cognitive and Brain Sciences, ’ Stephanstr. 1a, terase are reduced in patients with Alzheimer s disease 04103 Leipzig, Germany sparked the interest in the relationship between the 206 Psychopharmacology (2011) 215:205–229 cholinergic system and cognition, particularly due to the The cholinergic system fact that this decrease correlates with cognitive performance deficits (Bowen et al. 1976; Perry et al. 1978). Since these In the central nervous system, neurons that use the first findings, more extensive knowledge about the cholin- neurotransmitter acetylcholine (ACh) form the so-called ergic system and the different cholinergic receptors has cholinergic system. Cholinergic neurons form a contiguous been gained. Meanwhile, multiple cholinergic receptor aggregate of cells running from the cranial nerve nuclei of subtypes have been identified, and investigations into the the brain stem to the medullary tegmentum and pontome- involvement of the specific subtypes in cognition have sencephalic tegmentum, continuing rostrally through the advanced. diencephalon to the telencephalon (Woolf 1991). There are This review seeks to provide an overview of previous three major cholinergic subsystems in the brain, two of findings on the influence of cholinergic receptor manipu- which are projection systems with broad, diffuse and rather lations on cognition, with particular regard to the role of sparse innervation to wide areas of the brain. In these two selected cholinergic receptor subtypes. Furthermore, the projection systems, cholinergic neurons originate either involvement of these receptor subtypes in the regulation of from (1) various basal forebrain nuclei (particularly, the brain electrical activity as measured by electroencephalog- nucleus basalis Meynert), from where they innervate raphy (EEG) shall be addressed in order to evaluate the mainly the cortex (e.g. neocortex, cingulate cortex) and relationship between the cholinergic system and vigilance hippocampus, or (2) from brainstem nuclei (e.g. the regulation. pedunculopontine and laterodorsal tegmental nucleus), The term vigilance is used with various different from where they provide widespread innervation to the definitions depending on the scientific field, in which it thalamus and midbrain dopaminergic areas and also is used. Psychologists often refer to vigilance as descending innervation to the caudal pons and brain stem sustained attention. Here, we use the term “vigilance” (Dani and Bertrand 2007; Everitt and Robbins 1997; Thiel not to describe an attentionalconceptbuttoreferto and Fink 2007). The laterodorsal tegmental nucleus projects neurophysiological arousal as measured by EEG. With mainly to the ventral tegmental area; the pedunculopontine vigilance stages, we refer to different global states of nucleus innervates both the ventral tegmental area and the brainfunctionwhichcanbedelineatednotonlyduring substantia nigra (see also Maskos 2008; Mena-Segovia et sleep but also during wakefulness as transition states al. 2008; Sesack and Grace 2010). The cholinergic from high alertness to drowsiness. We consider this modulation of the midbrain dopamine system has been additional focus important since cognition and vigilance connected to nicotine self-administration in rats and hence (in terms of neurophysiological arousal) are interrelated. is thought to support drug reinforcement (see Maskos 2008, However, it is not quite clear how this interrelation is but see also Levin and Rose 1995 for interactions of the organised, i.e. whether both cognition and vigilance are cholinergic and dopaminergic system in terms of working directly influenced by the cholinergic system or whether memory performance). cognitive changes upon cholinergic manipulation are The third cholinergic subsystem arises from a collection only a result of a cholinergically induced change in of cholinergic interneurons in the striatum, which provides vigilance regulation. very dense local innervation. These interneurons contribute Cognitive aspects are not only influenced by a person’s about 1–3% of the striatal neurons and interact with the rich vigilance state either, but also by his or her affective state. dopaminergic innervation of the striatum arising from the Therefore, it seems most appropriate to think of an substantia nigra pars compacta and the ventral tegmental individual’s cognition, EEG vigilance and affective state area (Zhou et al. 2002). as partly overlapping and interacting domains, all of which There are two main classes of ACh receptors: muscarinic are also influenced by cholinergic interference. For example, (mAChR) and nicotinic receptors (nAChR). vigilance and the affective state influence cognition. In turn, cognitive processing has also been suggested to have an Muscarinic receptors influence on affect (e.g. Schachter and Singer 1962). Furthermore, there seems to be a link between vigilance Apart from being responsive to ACh, muscarinic receptors and affective state since vigilance patterns differ between also have a high affinity for muscarine. They are metabotropic various affective spectrum disorders (Hegerl et al. 2008b). receptors that act by coupling to G proteins (Caulfield 1993) This article shall provide an overview of clinical and and belong to a multigene family that also includes preclinical findings concerning the influence of the brain serotonin, norepinephrine, and dopamine receptors (Blake cholinergic system on these three domains, namely brain et al. 1991). electrical activity (as a measure of vigilance), cognition and Until now, cloning studies have identified five different emotion. genes (m1–m5) putatively encoding muscarinic receptor Psychopharmacology (2011) 215:205–229 207 subtypes. Consequently, it is assumed that there are also mation concerning the nicotinic acetylcholine receptors, refer five mAChR subtypes, M1 to M5 (Caulfield 1993; Hulme et to the book by Changeux and Edelstein (2005). al. 1990), although only M1 to M4 could be verified by pharmacological binding studies (Eglen et al. 1994). M1/ m1 is the most abundant subtype in cortex and hippocam- Vigilance regulation pus, while M2/m2 can be found mainly in brainstem, cerebellum and thalamus. Within the striatum, M4/m4 is In parallel to the transition from active wakefulness to deep most often found (Levey 1993). For further details on the sleep, the human brain takes on different global functional distribution of the muscarinic subtypes in the brain, see states. These functional states are reflected in the spectral Flynn et al. (1997) or Caulfield (1993). This review will composition and topography of the EEG and
Load more

Recommended publications
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • G Protein-Coupled Receptors As Therapeutic Targets for Multiple Sclerosis
    npg GPCRs as therapeutic targets for MS Cell Research (2012) 22:1108-1128. 1108 © 2012 IBCB, SIBS, CAS All rights reserved 1001-0602/12 $ 32.00 npg REVIEW www.nature.com/cr G protein-coupled receptors as therapeutic targets for multiple sclerosis Changsheng Du1, Xin Xie1, 2 1Laboratory of Receptor-Based BioMedicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sci- ences and Technology, Tongji University, Shanghai 200092, China; 2State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong New District, Shanghai 201203, China G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmit- ters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spec- trum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated de- myelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or phar- macological manipulations.
    [Show full text]
  • Current Advances in Allosteric Modulation of Muscarinic Receptors
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 18 January 2020 Peer-reviewed version available at Biomolecules 2020, 10, 325; doi:10.3390/biom10020325 Review Current Advances in Allosteric Modulation of Muscarinic Receptors Jan Jakubik 1* and Esam E. El-Fakahany 2* 1 Department of Neurochemistry, Institute of Physiology CAS, Prague, Czech Republic; [email protected] 2 Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA; [email protected] * Correspondence: [email protected]; [email protected] Abstract: Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes or chronic pulmonary obstruction. Here we review progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation and in vivo actions of in order to understand the translational impact of studying this important class of pharmacological agents. We overview newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents. Keywords: acetylcholine; muscarinic receptors; allosteric modulation 1. Introduction Slow metabotropic responses to acetylcholine are mediated by muscarinic receptors. Five distinct subtypes of muscarinic acetylcholine receptors (M1-M5) have been identified in the human genome[1].
    [Show full text]
  • Defects of the Glycinergic Synapse in Zebrafish
    fnmol-09-00050 June 28, 2016 Time: 16:28 # 1 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 29 June 2016 doi: 10.3389/fnmol.2016.00050 Defects of the Glycinergic Synapse in Zebrafish Kazutoyo Ogino* and Hiromi Hirata* Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara, Japan Glycine mediates fast inhibitory synaptic transmission. Physiological importance of the glycinergic synapse is well established in the brainstem and the spinal cord. In humans, the loss of glycinergic function in the spinal cord and brainstem leads to hyperekplexia, which is characterized by an excess startle reflex to sudden acoustic or tactile stimulation. In addition, glycinergic synapses in this region are also involved in the regulation of respiration and locomotion, and in the nociceptive processing. The importance of the glycinergic synapse is conserved across vertebrate species. A teleost fish, the zebrafish, offers several advantages as a vertebrate model for research of glycinergic synapse. Mutagenesis screens in zebrafish have isolated two motor defective mutants that have pathogenic mutations in glycinergic synaptic transmission: bandoneon (beo) and shocked (sho). Beo mutants have a loss-of-function mutation of glycine receptor (GlyR) b-subunit b, alternatively, sho mutant is a glycinergic transporter 1 (GlyT1) defective mutant. These mutants are useful animal models for understanding of glycinergic synaptic transmission and for identification of novel therapeutic agents for human diseases arising from defect in glycinergic transmission, such as hyperekplexia or glycine encephalopathy. Recent advances in techniques for genome editing and for Edited by: Robert J.
    [Show full text]
  • Contractile Effects and Receptor Analysis of Adenosine-Receptors in Human Detrusor Muscle from Stable and Neuropathic Bladders
    Naunyn-Schmiedeberg's Arch Pharmacol (2016) 389:921–929 DOI 10.1007/s00210-016-1255-1 ORIGINAL ARTICLE Contractile effects and receptor analysis of adenosine-receptors in human detrusor muscle from stable and neuropathic bladders Mahreen Pakzad1 & Youko Ikeda 1 & Carly McCarthy1 & Darryl G. Kitney1,2 & Rita I. Jabr1,3 & Christopher H. Fry1,2 Received: 15 March 2016 /Accepted: 26 April 2016 /Published online: 17 May 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract To measure the relative transcription of adenosine by alloxazine) only in guinea-pig tissue. Adenosine receptor receptor subtypes and the contractile effects of adenosine and subtype transcription was measured in human detrusor and selective receptor-subtype ligands on detrusor smooth muscle was similar in both groups, except reduced A2A levels in from patients with neuropathic overactive (NDO) and stable overactive bladder. Suppression of the carbachol contracture bladders and also from guinea-pigs. Contractile function was in human detrusor is independent of A-receptor activation, in measured at 37°C in vitro from detrusor smooth muscle strips. contrast to an A2B-dependent action with guinea-pig tissue. Contractions were elicited by superfusate agonists or by elec- Adenosine also reduced nerve-mediated contractions, by an trical field stimulation. Adenosine-receptor (A1, A2A, A2B, A1- dependent action suppressing ATP neurotransmitter A3) transcription was measured by RT-PCR. Adenosine atten- action. uated nerve-mediated responses with equivalent efficacy in human and guinea-pig tissue (pIC50 3.65–3.86); the action Keywords Adenosine . neuropathic bladder . detrusor . was more effective at low (1–8 Hz) compared to high (20– contraction .
    [Show full text]
  • Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators
    International Journal of Molecular Sciences Review Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators Manuel Grundmann 1,* , Eckhard Bender 2, Jens Schamberger 2 and Frank Eitner 1 1 Research and Early Development, Bayer Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany; [email protected] 2 Drug Discovery Sciences, Bayer Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany; [email protected] (E.B.); [email protected] (J.S.) * Correspondence: [email protected] Abstract: The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because Citation: Grundmann, M.; Bender, of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of E.; Schamberger, J.; Eitner, F.
    [Show full text]
  • Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control
    Physiol Rev 92: 193–235, 2012 doi:10.1152/physrev.00043.2010 FAST SYNAPTIC INHIBITION IN SPINAL SENSORY PROCESSING AND PAIN CONTROL Hanns Ulrich Zeilhofer, Hendrik Wildner, and Gonzalo E. Yévenes Institute of Pharmacology and Toxicology, University of Zurich, and Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland Zeilhofer HU, Wildner H, Yévenes GE. Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control. Physiol Rev 92: 193–235, 2012; doi:10.1152/physrev.00043.2010.— The two amino acids GABA and glycine mediate fast inhibitory neurotransmission in different CNS areas and serve pivotal roles in the spinal sensory processing. Under healthy conditions, they limit the excitability of spinal terminals of primary sensory nerve Lfibers and of intrinsic dorsal horn neurons through pre- and postsynaptic mechanisms, and thereby facilitate the spatial and temporal discrimination of sensory stimuli. Removal of fast inhibition not only reduces the fidelity of normal sensory processing but also provokes symptoms very much reminiscent of pathological and chronic pain syndromes. This review summarizes our knowledge of the molecular bases of spinal inhibitory neurotransmission and its organization in dorsal horn sensory circuits. Particular emphasis is placed on the role and mechanisms of spinal inhibitory malfunction in inflammatory and neuropathic chronic pain syndromes. I. INTRODUCTION 193 the spinal terminals of primary sensory fibers through post- II. MOLECULAR COMPOSITION OF FAST... 194 synaptic and presynaptic mechanisms. The function of in- III. LAMINAR ORGANIZATION OF THE... 198 hibitory dorsal horn neurons, however, extends far beyond IV. LAMINAR DISTRIBUTION OF GABAA... 200 the physiological processing of somatosensory stimuli and V. DISTRIBUTION OF PRESYNAPTIC..
    [Show full text]
  • Evaluation of the Pharmacological Activities of RAD1901, a Selective Estrogen Receptor Degrader
    S E Wardell et al. Relative agonist/antagonist 22:5 713–724 Research activity of RAD1901 Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader Suzanne E Wardell, Erik R Nelson*, Christina A Chao, Holly M Alley and Donald P McDonnell Correspondence Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Box 3813, Durham, should be addressed North Carolina 27710, USA to D P McDonnell *E R Nelson is now at Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Email 523 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801, USA [email protected] Abstract Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains a first-line treatment Key Words for estrogen receptor 1 (ESR1) positive breast cancer. However, tumor resistance limits the " selective estrogen receptor duration of response. The clinical efficacy of fulvestrant, a selective ER degrader (SERD) that degrader triggers receptor degradation, has confirmed that ESR1 often remains engaged in endocrine " SERM therapy resistant cancers. Recently developed, selective ER modulators (SERMs)/SERD hybrids " endocrine-resistant breast cancer (SSHs) that facilitate ESR1 degradation in breast cancer cells and reproductive tissues have " RAD1901 been advanced as an alternative treatment for advanced breast cancer, particularly in the metastatic setting. RAD1901 is one SSH currently being evaluated clinically that is unique Endocrine-Related Cancer among ESR1 modulators in that it readily enters the brain, a common site of breast cancer metastasis. In this study, RAD1901 inhibited estrogen activation of ESR1 in vitro and in vivo, inhibited estrogen-dependent breast cancer cell proliferation and xenograft tumor growth, and mediated dose-dependent downregulation of ESR1 protein.
    [Show full text]
  • Repurposing the Estrogen Receptor Modulator Raloxifene to Treat SARS
    www.nature.com/cdd REVIEW ARTICLE OPEN Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 infection ✉ Marcello Allegretti 1 , Maria Candida Cesta 1, Mara Zippoli1, Andrea Beccari1, Carmine Talarico1, Flavio Mantelli1, Enrico M. Bucci 2, Laura Scorzolini3 and Emanuele Nicastri3 © The Author(s) 2021 The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients. Cell Death & Differentiation; https://doi.org/10.1038/s41418-021-00844-6 FACTS (3) If successful, the ongoing clinical study on raloxifene, a well- known SERM, in paucisymptomatic COVID-19 patients could represent a valid opportunity of treatment for controlling (1) Despite the recent advancements in vaccines development, disease progression. it is still essential not to underestimate the risk associated (4) Validation of the running hypothesis would pave the way for with COVID-19 infection, and to advance knowledge on further investigation on ER modulation as therapeutic specific SARS-CoV-2 pharmacological treatments to cure or approach to treat other infectious diseases.
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptExpert Opin Author Manuscript Investig Drugs Author Manuscript . Author manuscript; available in PMC 2016 January 21. Published in final edited form as: Expert Opin Investig Drugs. 2014 February ; 23(2): 243–254. doi:10.1517/13543784.2014.852536. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists Joseph R Moskal, PhD†,1, Ronald Burch2, Jeffrey S Burgdorf1, Roger A Kroes1, Patric K Stanton3, John F Disterhoft1, and J David Leander2 1Northwestern University, McCormick School of Engineering and Applied Science, Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, 1801 Maple Avenue, Suite 4300, Evanston IL 60201, USA 2Naurex Inc., Evanston, IL, USA 3New York Medical College, Department of Cell Biology & Anatomy, Valhalla, NY, USA Abstract Introduction—The N-methyl-D-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-D-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects. Areas covered—The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies. Expert opinion—NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic.
    [Show full text]
  • Aptinyx to Present Preclinical Data for NMDA Receptor Modulators in Neurologic Disorders at Neuroscience 2017
    Aptinyx to Present Preclinical Data for NMDA Receptor Modulators in Neurologic Disorders at Neuroscience 2017 November 14, 2017 Evanston, Ill., November 14, 2017 – Aptinyx Inc., a clinical-stage biopharmaceutical company developing transformative therapies for challenging neurologic disorders, today announced the presentation of results from several studies of novel N-methyl-D-aspartate (NMDA) receptor modulators in models of neuropathic pain, post-traumatic stress disorder (PTSD), cognition and traumatic brain injury at Neuroscience 2017, the annual meeting of the Society for Neuroscience, November 11-15, 2017 in Washington, D.C. “These data demonstrate the diversity of Aptinyx’s drug discovery programs and continue to illustrate the broad applicability of modulating NMDA receptors in treating neurologic disorders,” said Joseph Moskal, Ph.D., chief scientific officer of Aptinyx. Presentation Details Enhancement of synaptic plasticity by NYX-2925: Sleep cycle EEG studies in rats (Poster #72.14 / KK18) Presenter: Jeffrey S. Burgdorf, director of discovery science at Aptinyx Presentation Date & Time: Saturday, November 11, 2017 – 1:00 – 5:00 p.m. ET • Summary: Brain activity in sleep deprived rats dosed with NYX-2925 demonstrated significantly facilitated slow wave sleep, suggesting NYX-2925 has the potential to improve sleep quality and decrease symptoms of sleep disruption caused by sleep deprivation. NYX-2925, a novel NMDA receptor modulator, reversed cognitive impairment induced by either aging or scopolamine (Poster #129.01 / P8) Presenter: Amanda Gross, senior research scientist at Aptinyx Presentation Date & Time: Sunday, November 12, 2017 – 8:00 – 12:00 p.m. ET • Summary: Results from two models of cognitive impairment suggest that NYX-2925 has therapeutic potential for treating cognition deficient-related disorders.
    [Show full text]
  • FDA Listing of Established Pharmacologic Class Text Phrases January 2021
    FDA Listing of Established Pharmacologic Class Text Phrases January 2021 FDA EPC Text Phrase PLR regulations require that the following statement is included in the Highlights Indications and Usage heading if a drug is a member of an EPC [see 21 CFR 201.57(a)(6)]: “(Drug) is a (FDA EPC Text Phrase) indicated for Active Moiety Name [indication(s)].” For each listed active moiety, the associated FDA EPC text phrase is included in this document. For more information about how FDA determines the EPC Text Phrase, see the 2009 "Determining EPC for Use in the Highlights" guidance and 2013 "Determining EPC for Use in the Highlights" MAPP 7400.13.
    [Show full text]