DOCSLIB.ORG

Enhancement of Specific [3Hlquipazine Binding with Triton X-100-Treated Membranes from Rat Cortex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Enhancement of Specific [3Hlquipazine Binding with Triton X-100-Treated Membranes from Rat Cortex Improvement of 5-HT3 Receptor Binding Assay: Enhancement of Specific [3HlQuipazine Binding with Triton X-100-Treated Membranes from Rat Cortex Teruaki Une, Kiyoshi Furukawa and Masanobu Komiya Department of Pharmacology, Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94, Enokicho, Suita, Osaka 564, Japan Received April 9, 1991 Accepted July 1, 1991 ABSTRACT-The 5-hydroxytryptamine (5-HT)3 receptor binding assay using [3H]quipazine was examined. It was impossible to obtain specific [3H]quipazine bind ing with the membrane fractions from rat cortex prepared by the usual procedure. When the membranes were pretreated with detergent Triton X-100, the ratio of spe cific [3H]quipazine binding markedly increased, depending upon the concentration of Triton X-100 in the range of 0.01-0.1% (w/v). At a concentration of more than 0.05%, the specific binding reached a maximum of 55 to 60% of the total binding. The specific [3H]quipazine binding to the Triton X-100-treated membranes was re versible and was potently inhibited by several 5-HT3 antagonists, while 5-HT], 5-HT2 receptor antagonists and other receptor-specific ligands had no effect on the binding. Scatchard analysis indicated a single class of binding sites with a Kd of 0.62 nM and Bmax of 97 fmol/mg protein. Thus, the Triton X-100-treated membranes retained the characteristics of 5-HT3 binding sites, making it possible to use [3H]quipazine for a 5 HT3 receptor binding assay with a high ratio of specific binding. Serotonin (5-HT) receptors have been di their method, because of high percentages of vided into three different subtypes: 5-HT1, 5 non-specific binding. To obtain 5-HT3 recep HT2 and 5-HT3 (1). Recently, the binding tor preparations with a high affinity for sites of 5-HT3 in the central nervous system [3H]quipazine, we performed various addition have been identified by radioligand binding al treatments on the membranes; and inter techniques using tritium-labeled 5-HT3 antago estingly, we found that the specific binding of nists such as [3H]GR65630 (2), [3H]zacopride [3H]quipazine increased markedly when the (3), [3H]BRL 43694 (4), [3H]LY278584 (5) membranes were treated with Triton X-100 and [3H]GR67330 (6). (polyethylene glycol p-isooctylphenyl ether). Peroutka and Hamik (7) have reported that In the present paper, we describe a reliable [3H]quipazine, a commercially available radio method for 5-HT3 receptor binding assay with ligand, has a high affinity for 5-HT3 binding [3H]quipazine using Triton X-100-treated mem sites in rat cortical membranes. However, we branes of the rat cortex. have been unsuccessful in attempts to obtain A preliminary account of these findings has highly specific [3H]quipazine binding using been presented at the 63rd Annual Meeting of the Japanese Pharmacological Society (8). scintillation cocktail (Amersham). Specific binding was defined as the excess over blanks MATERIALS AND METHODS taken in the presence of 1 uM BRL 43694. Protein concentration was determined by the Preparation of membranes method of Lowry et al. (9) using bovine serum Male Std-Wistar rats (200-250 g) were de albumin as a standard. capitated. The frontal cortex was dissected and homogenized in 10 volumes of ice-cold Drugs 0.32 M sucrose in a Potter-Elvehjem glass The following compounds were used: homogenizer fitted with a Teflon pestle. The [3H]quipazine (Dupont New England Nuclear, homogenate was centrifuged at 1000 X g for Specific Activity = 68.1 Ci/mmol); serotonin 10 min and the pellet was discarded. The su creatinine sulfate (Merck); metoclopramide pernatant was centrifuged at 17,200 X g for 10 hydrochloride, 1-alprenolol (Sigma); clonidine min. The crude mitochondrial pellet was re hydrochloride, spiperone, SCH23390, amitrip suspended in 20 volumes of Krebs-HEPES tyline hydrochloride (RBI), methysergide buffer and centrifuged at 17,200 X g for 10 maleate (extracted from Sansert, Sandoz); min. The pellet (fraction P2) was resuspended cisapride (extracted from Acenaline, Janssen in 20 volumes of Krebs-HEPES buffer con Kyowa); and ICS 205-930, BRL 43694, BRL taining 0.01-0.1% Triton X-100. After a 30 24924, GR38032F, MDL 72222, 2-methyl-5 min incubation at 37°C, the membranes were hydroxytryptamine maleate (synthesized in our washed twice by recentrifuging (50,000 X g, laboratories). 15 min) and resuspending in Triton X-100-free buffer (Krebs-HEPES buffer). The pellet was RESULTS finally suspended in 40 volumes of the same buffer. A Krebs-HEPES buffer consisting of Effect of treatment of rat cortical membranes 25 mM HEPES, 180 mM NaCl, 5 mM KCI, with Triton X-100 on [3H]quipazine binding 2.5 mM CaCl2 and 1.2 mM MgCl2 (pH ad The fraction P2 prepared from rat cortex justed to 7.4) was used. was incubated with 1.0 nM [3H]quipazine. No significant amount of specific [3H]quipazine Binding assay binding could be detected, because the non Krebs-HEPES buffer (500,ul) with or with specific binding of [3H]quipazine was very out the drug, was added to assay tubes and high. Although the amount and proportion of 100 ul of [3H]quipazine was added at final the specific binding varied in different batchs concentrations of 1.0 nM and 0.3 4.0 nM for of [3H]quipazine, the specific binding was less drug competition and saturation studies, re than 30% of the total binding. To remove spectively. Subsequently, the membrane sus possible endogenous serotonin from the mem pension (0.2 mg protein/400 ul) was added to branes, the membrane preparation (fraction initiate binding. The assay tubes were incu P2) was incubated for 30 min at 37°C in bated for 30 min at 25°C. The incubation was Krebs-HEPES buffer, pH 7.4. The specific terminated by rapid filtration under reduced [3H]quipazine binding increased slightly with pressure through Whatman GF/B filters pre increasing total [3H]quipazine binding. soaked in 0.03% polyethyleneimine. The fil When the membrane preparation was incu ters were immediately washed three times with bated for 30 min at 37°C in Triton X-100 solu 4 ml of ice-cold 50 mM Tris-HC1 buffer (pH tion and washed with Triton X-100-free buffer 7.7). by centrifugation twice, the ratio of specific All experiments were performed in dupli [3H]quipazine binding to the Triton X-100 cate or triplicate. Radioactivity was measured treated membranes markedly increased. As by liquid scintillation counting in 10 ml ACS II shown in Table 1, the increases in the ratio of Table 1. Effect of Triton X-100 treatment on specific [3H]quipazine binding specific binding were dependent on the con centration of Triton X-100 in the range of 0.01 -0 .1%. The treatment with more than 0.05% Triton X-100 gave maximal specific binding that was 55 60% of the total binding at 1.0 nM [3H]quipazine. In preliminary experiments a remarkable decrease of specific binding was observed when the membranes were treated with more than 0.1% Triton X-100, such as 0.3% (data not shown). These effects of Tri ton X-100 treatment were observed consistent ly with any batch of [3H]quipazine. Characterization of Triton X-100-treated mem branes The binding of [3H]quipazine to 5-HT3 bind ing sites in Triton X-100-treated membranes Fig. 1. The linearity of the specific binding of 1.0 nM was assessed. [3H]quipazine to the Triton X-100-treated membranes. The amount of the specific [3H]quipazine binding was linear over a range of membrane 0.99. It revealed a homogeneous population of protein (25 500 ,ug protein per tube, Fig. 1). [3H]quipazine binding sites having a Kd value In saturation analysis of [3H]quipazine bind of 0.62 ± 0.01 nM and Bmax value of 97 ± 6.9 ing, the specific binding increased with concen fmol/mg protein. trations ranging from 0.3 to 2 nM [3H]quipazine Kinetic analysis of [3H]quipazine binding and reached a saturation at higher concentra demonstrated that [3H]quipazine associated tions (Fig. 2). Scatchard transformation of rapidly with the specific binding sites (K+t = these data was linear with a coefficient of 7.64 X 106/M/s); and once equilibrium had been reached, the binding was shown to be In drug competition studies, selective 5-HT3 completely reversible by the addition of 1 u M antagonists, zacopride, ICS 205-930, BRL BRL 43694 to initiate dissociation (K_1 = 43694, GR38032F, BRL 24924 and MDL 72222, 6.36 X 10-3/s, Fig. 3). The Kd (= K+1/K1) potently inhibited the specific [3H]quipazine calculated from these rate constants gave a binding at subnanomolar to nanomolar con value of 0.83 nM. This Kd value was in close centrations (Table 2). All competition curves agreement with that obtained from Scatchard were steep and monophasic. Nonselective 5 analysis. HT3 antagonists, metoclopramide and cisa Fig. 2. The saturation analysis of binding of [3H]quipazine (0.3-4.0 nM) to the Triton X-100 (0.05%) treated membranes. (A) shows the saturation curve for the binding of [3H]quipazine. Symbols represent (0) total, (A) specific and (0) non-specific binding. Non-specific binding was defined with 1 uM BRL 43694. (B) shows the Scatchard transformation of these data. The correlation coefficient was 0.99. Fig. 3. The association (40) and dissociation (0) induced by BRL 43694 of [3H]quipazine binding to the Triton X-100 (0.05%)-treated membranes. The membranes were incubated with 1.0 nM [3H]quipazine for the indicated times at 25°C. After a 30-min incubation, the dissociation was induced by an addition (arrow) of 1 u M BRL 43694.
Load more

Recommended publications
  • The Uptake and Release of Serotonin and Dopamine Associated with Locust (Locusta Migratoria) Salivary Glands
    The Journal of Experimental Biology 199, 699–709 (1996) 699 Printed in Great Britain © The Company of Biologists Limited 1996 JEB0166 THE UPTAKE AND RELEASE OF SEROTONIN AND DOPAMINE ASSOCIATED WITH LOCUST (LOCUSTA MIGRATORIA) SALIVARY GLANDS DECLAN W. ALI AND IAN ORCHARD Department of Zoology, 25 Harbord Street, University of Toronto, Toronto, Ontario, Canada M5S 1A1 Accepted 24 October 1995 Summary The uptake and release characteristics of dopamine and affinity components. [3H]dopamine uptake is Na+- serotonin in the salivary glands of the locust Locusta independent and can be partially reduced by a challenge migratoria were examined. Cyclic AMP levels were with high-K+ saline and by a challenge with ice-cold saline. determined in salivary glands in which the salivary nerve Uptake inhibitors are capable of blocking the uptake of was stimulated under different experimental paradigms. radiolabelled serotonin and dopamine. There is a Ca2+- Stimulation of the salivary nerve leads to time- and dependent efflux of [3H]serotonin and [3H]dopamine from frequency-dependent elevations of cyclic AMP levels in the previously loaded salivary glands in response to glands. The potent and specific D1 receptor antagonist stimulation of the salivary nerve and to treatment with a SCH-23390 is capable of partially inhibiting the high-K+ saline. electrophysiologically induced elevations of cyclic AMP levels. The salivary glands appear to possess uptake transporters for serotonin and dopamine. [3H]serotonin Key words: salivary glands, insect, dopamine, serotonin, cyclic AMP, uptake is Na+-dependent and is composed of high- and low- uptake, release, locust, Locusta migratoria. Introduction Locust salivary glands are innervated via the salivary nerve, evidence to suggest that dopamine and serotonin alter salivary nerve 7b, which is a branch of nerve 7 that originates from the secretory rates (Baines et al.
    [Show full text]
  • Synthesis of Novel 6-Nitroquipazine Analogs for Imaging the Serotonin Transporter by Positron Emission Tomography
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2006 Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography David B. Bolstad The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Bolstad, David B., "Synthesis of novel 6-nitroquipazine analogs for imaging the serotonin transporter by positron emission tomography" (2006). Graduate Student Theses, Dissertations, & Professional Papers. 9590. https://scholarworks.umt.edu/etd/9590 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. Maureen and Mike MANSFIELD LIBRARY The University of Montana Permission is granted by the author to reproduce this material in its entirety, provided that this material is used for scholarly purposes and is properly cited in published works and reports. **Please check "Yes" or "No" and provide signature** Yes, I grant permission No, I do not grant permission Author's Signature: Date: C n { ( j o j 0 ^ Any copying for commercial purposes or financial gain may be undertaken only with the author's explicit consent. 8/98 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
    [Show full text]
  • Skim - a Generalized Literature-Based Discovery System For
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.16.343012; this version posted October 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SKiM - A generalized literature-based discovery system for uncovering novel biomedical knowledge from PubMed Kalpana Raja1, John Steill1, Ian Ross2, Lam C Tsoi3,4,5, Finn Kuusisto1, Zijian Ni6, Miron Livny2, James Thomson1,7 and Ron Stewart1* 1Regenerative Biology, Morgridge Institute for Research, Madison, WI, USA 2Center for High Throughput Computing, Computer Sciences Department, University of Wisconsin, Madison, WI, USA 3Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA 4Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA 5Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA 6Department of Statistics, University of Wisconsin, Madison, WI, USA 7Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, USA *Corresponding author Email: [email protected] Phone: (608) 316-4349 Home page: https://morgridge.org/profile/ron-stewart/ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.16.343012; this version posted October 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Literature-based discovery (LBD) uncovers undiscovered public knowledge by linking terms A to C via a B intermediate. Existing LBD systems are limited to process certain A, B, and C terms, and many are not maintained. We present SKiM (Serial KinderMiner), a generalized LBD system for processing any combination of A, Bs, and Cs.
    [Show full text]
  • Antidepressant Potential of Nitrogen-Containing Heterocyclic Moieties: an Updated Review
    Review Article Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review Nadeem Siddiqui, Andalip, Sandhya Bawa, Ruhi Ali, Obaid Afzal, M. Jawaid Akhtar, Bishmillah Azad, Rajiv Kumar Department of ABSTRACT Pharmaceutical Chemistry, Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is Faculty of Pharmacy, Jamia Hamdard approved for the treatment of major depression (including paediatric depression), obsessive-compulsive University, Hamdard disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual Nagar, New Delhi - dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as 110 062, India major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a Address for correspondence: risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing Dr. Sandhya Bawa, E-mail: sandhyabawa761@ treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of yahoo.com literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression. Received : 08-02-11 Review completed : 15-02-11 Accepted : 17-02-11 KEY WORDS: Antidepressant, depression, heterocyclic epression is a chronic, recurring and potentially life- monoamine oxidase inhibitors (MAOIs, e.g. Nardil®) tricyclic D threatening illness that affects up to 20% of the population antidepressants (TCAs, e.g. Elavil). They increases the synaptic across the globe.[1] The etiology of the disease is suboptimal concentration of either two (5-HT and NE) or all three (5-HT, concentrations of the monoamine neurotransmitters serotonin NE and dopamine (DA)) neurotransmitters.
    [Show full text]
  • Serotonergic Activiation of Locomotor Behavior and Posture in One-Day
    Behavioural Brain Research 302 (2016) 104–114 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Serotonergic activation of locomotor behavior and posture in one-day old rats ∗ Hillary E. Swann, R. Blaine Kempe, Ashley M. Van Orden, Michele R. Brumley Idaho State University, Department of Psychology, Pocatello, ID, United States h i g h l i g h t s • Quipazine induced air-stepping, locomotion, and posture in P1 rats. • During air-stepping, steps maintained highly anti-phase coordination. • Forms of locomotion included pivoting, crawling, and some walking. • Advanced posture such as head elevation and locomotor stances were shown. a r t i c l e i n f o a b s t r a c t Article history: The purpose of this study was to determine what dose of quipazine, a serotonergic agonist, facilitates Received 11 July 2015 air-stepping and induces postural control and patterns of locomotion in newborn rats. Subjects in both Received in revised form experiments were 1-day-old rat pups. In Experiment 1, pups were restrained and tested for air-stepping 18 November 2015 in a 35-min test session. Immediately following a 5-min baseline, pups were treated with quipazine (1.0, Accepted 5 January 2016 3.0, or 10.0 mg/kg) or saline (vehicle control), administered intraperitoneally in a 50 ␮L injection. Bilateral Available online 12 January 2016 alternating stepping occurred most frequently following treatment with 10.0 mg/kg quipazine, however the percentage of alternating steps, interlimb phase, and step period were very similar between the 3.0 Keywords: and 10.0 mg/kg doses.
    [Show full text]
  • A Validated Animal Model for the Serotonin Syndrome
    A validated animal model for the Serotonin Syndrome Inaugural–Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Robert Haberzettl from Berlin, Germany 2014 This thesis is based on research conducted from 2008 to 2014 at the Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, in Berlin, Germany, under the supervision of Prof. Dr. med. Heidrun Fink and Dr. vet. med. Bettina Bert. Reviewer 1. Reviewer: Prof. Dr. med. Heidrun Fink Institute of Pharmacology and Toxicology Department of Veterinary Medicine Freie Universität Berlin 2. Reviewer: Prof. Constance Scharff, PhD Institute of Biology Department of Biology, Chemistry and Pharmacy Freie Universität Berlin Date of defence: 24.06.2015 ii Declaration I hereby declare that the work presented in this thesis has been conducted independently and without any inappropriate support, and that all sources of content, experimental or intellectual, are suitably referenced and acknowledged. I further declare that this thesis has not been submitted before, either in the same or a different form, to this or any other university for a degree. Robert Haberzettl Berlin, den 01.09.2014 iii Acknowledgement My sincere gratitude goes to Professor Dr. Heidrun Fink, who gave me the opportunity to work in her institute and guided me throughout the entire doctoral period. I have learned much in the field of science but also a lot about life. To Dr. Bettina Bert, I am grateful for her guidance and support. Dr. Jan Brosda, Dr. Nicole Marquardt and Alexandra Wiczorek, I am grateful for your help, advice and friendship.
    [Show full text]
  • 5-HT Receptors Review
    Neuronal 5-HT Receptors and SERT Nicholas M. Barnes1 and John F. Neumaier2 1Cellular and Molecular Neuropharmacology Research Group, Section of Neuropharmacology and Neurobiology, Clinical and Experimental Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT UK and 2Department of Psychiatry, University of Washington, Seattle, WA 98104 USA. Correspondence: [email protected] and [email protected] Nicholas Barnes is Professor of Neuropharmacology at the University of Birmingham Medical School, and focuses on serotonin receptors and the serotonin transporter. John Neumaier is Professor of Psychiatry and Behavioural Sciences and Director of the Division of Neurosciences at the University of Washington. His research concerns the role of serotonin receptors in emotional behavior. Contents Introduction Introduction ........................................................................ 1 5-hydroxytryptamine (5-HT, serotonin) is an ancient biochemical manipulated through evolution to be DRIVING RESEARCH FURTHER The 5-HT1 Receptor Family ............................................... 1 utilized extensively throughout the animal and plant kingdoms. Mammals employ 5-HT as a 5-HT Receptors ............................................................ 2 1A neurotransmitter within the central and peripheral nervous systems, and also as a local hormone in 5-HT Receptors ............................................................ 2 1B numerous other tissues, including the gastrointestinal tract, the cardiovascular
    [Show full text]
  • Sexual Dysfunction, Depression and Antidepressants: a Translational Approach
    Chapter 4 Sexual Dysfunction, Depression and Antidepressants: A Translational Approach Jocelien D.A. Olivier, Diana C. Esquivel Franco, Marcel D. Waldinger and Berend Olivier Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.69105 Abstract Major depression is frequently associated with sexual dysfunctions. Most antidepres- sants, especially selective serotonin reuptake inhibitors (SSRIs), induce additional sexual side effects and, although effective antidepressants, deteriorate sexual symptoms, which are the main reason that patients stop antidepressant treatment. Many strategies have been used to circumvent the additional sexual side effects, but results are rather disap- pointing. Recently, new antidepressants have been introduced, vilazodone and vortiox- etine, which seem to lack sexual side effects in the early registration trials. Much research with large numbers of depressed patients and adequate methodological tools still has to confirm in daily use the absence of sexual side effects of new antidepressants. Animal models that in an early phase of drug development may predict putative sexual side effects of new antidepressants are extremely useful and could speed up development of new antidepressants. A rat model of sexual behavior is described that has a very high predictive validity for sexual side effects in man. Several characteristics of present antide- pressants with regard to sexual dysfunctions are also present in the rat model and estab- lish its validity. The animal model can also be used in the search for new psychotropics without sexual side effects or for drugs with sexual stimulating activity. Keywords: depression, sexual dysfunction, antidepressants, sexual side effects, SSRI, animal model 1.
    [Show full text]
  • Multi-Discipline Review
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 209500Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone) NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 209500 Priority or Standard Standard Submit Date(s) September 27, 2018 Received Date(s) September 27, 2018 PDUFA Goal Date December 27, 2019 Division/Office Division of Psychiatry / Office of Drug Evaluation-I Review Completion Date December 20, 2019 Established/Proper Name Lumateperone (Proposed) Trade Name Caplyta Pharmacologic Class Atypical Antipsychotic Code name ITI-007 Applicant Intra-Cellular Therapies, Inc. Dosage form 42 mg Capsules Applicant proposed Dosing 42 mg by mouth once daily Regimen Applicant Proposed Schizophrenia/Adults Indication(s)/Population(s) Applicant Proposed 58214004 | Schizophrenia (disorder) SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Schizophrenia/Adults Indication(s)/Population(s) (if applicable) Recommended SNOMED 58214004 | Schizophrenia (disorder) CT Indication Disease Term for each Indication (if applicable) Recommended Dosing 42 mg by mouth once daily Regimen 1 Version date: October 12, 2018 Reference ID: 4537404 NDA 209500 Multi-disciplinary Review and Evaluation Caplyta (lumateperone) Table of Contents Table of
    [Show full text]
  • Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission R ICHARD A
    Chapter 11 Serotonin Receptors and Drugs Affecting Serotonergic Neurotransmission R ICHARD A. GLENNON AND MAŁGORZATA DUKAT Drugs Covered in This Chapter* Antiemetic drugs (5-HT3 receptor • Rizatriptan • Imipramine antagonists) • Sumatriptan • Olanzapine • Alosetron • Zolmitriptan • Propranolol • Dolasetron Drug for the treatment of • Quetiapine • Granisetron irritable bowel syndrome (5-HT4 • Risperidone • Ondansetron agonists) • Tranylcypromine • Palonosetron • Tegaserod • Trazodone • Tropisetron Drugs for the treatment of • Ziprasidone Drugs for the treatment of neuropsychiatric disorders • Zotepine migraine (5-HT1D/1F receptor agonists) • Buspirone Hallucinogenic agents • Almotriptan • Citalopram • Lysergic acid diethylamide • Eletriptan • Clozapine • 2,5-dimethyl-4-bromoamphetamine • Frovatriptan • Desipramine • 2,5-dimethoxy-4-iodoamphetamine • Naratriptan • Fluoxetine Abbreviations cAMP, cyclic adenosine IBS-C, irritable bowel syndrome with nM, nanomoles/L monophosphate constipation MT, melatonin CNS, central nervous system IBS-D, irritable bowel syndrome with MTR, melatonin receptor 5-CT, 5-carboxamidotryptamine diarrhea NET, norepinephrine reuptake transporter DOB, 2,5-dimethyl-4-bromoamphetamine LCAP, long-chain arylpiperazine 8-OH DPAT, 8-hydroxy-2-(di-n- DOI, 2,5-dimethoxy-4-iodoamphetamine L-DOPA, L-dihydroxyphenylalanine propylamino)tetralin EMDT, 2-ethyl-5-methoxy-N,N- LSD, lysergic acid diethylamide PMDT, 2-phenyl-5-methoxy-N,N- dimethyltryptamine MAO, monomaine oxidase dimethyltryptamine GABA, g-aminobutyric acid MAOI,
    [Show full text]
  • Neuronal 5-HT Receptors and SERT
    NeuronalTocris 5-HT Scientific Receptors Review and SERTSeries Tocri-lu-2945 Neuronal 5-HT Receptors and SERT Nicholas M. Barnes1 and Introduction 2 John F. Neumaier 5-hydroxytryptamine (5-HT, serotonin) is an ancient biochemical 1Cellular and Molecular Neuropharmacology Research Group, manipulated through evolution to be utilized extensively Section of Neuropharmacology and Neurobiology, Clinical and throughout the animal and plant kingdoms. Mammals employ Experimental Medicine, The Medical School, University of 5-HT as a neurotransmitter within the central and peripheral Birmingham, Edgbaston, Birmingham B15 2TT, UK and nervous systems, and also as a local hormone in numerous other tissues, including the gastrointestinal tract, the cardiovascular 2Department of Psychiatry, University of Washington, Seattle, WA system and immune cells. This multiplicity of function implicates 98104, USA. Correspondence: [email protected] and 5-HT in a vast array of physiological and pathological processes. [email protected] This plethora of roles has consequently encouraged the Nicholas Barnes is Professor of Neuropharmacology at the development of many compounds of therapeutic value, including University of Birmingham Medical School, and focuses on various antidepressant, antipsychotic and antiemetic drugs. serotonin receptors and the serotonin transporter. John Neumaier Part of the ability of 5-HT to mediate a wide range of actions arises is Professor of Psychiatry and Behavioural Sciences and Director from the imposing number of 5-HT receptors.1 of the Division of Neurosciences at the University of Washington. Numerous 5-HT His research concerns the role of serotonin receptors in emotional receptor families and subtypes have evolved. Currently, 18 genes behavior. are recognized as being responsible for 14 distinct mammalian 5-HT receptor subtypes, which are divided into 7 families, all but one of which are members of the G-protein coupled receptor (GPCR) superfamily.
    [Show full text]
  • Antagonism of Nicotinic Acetylcholine Receptors by Inhibitors of Monoamine Uptake HE Lo´Pez-Valde´S and J Garcı´A-Colunga
    Molecular Psychiatry (2001) 6, 511–519 2001 Nature Publishing Group All rights reserved 1359-4184/01 $15.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Antagonism of nicotinic acetylcholine receptors by inhibitors of monoamine uptake HE Lo´pez-Valde´s and J Garcı´a-Colunga Centro de Neurobiologı´a, Universidad Nacional Auto´noma de Me´xico, Campus Juriquilla, Apartado Postal 1–1141, Juriquilla, Quere´taro 76001, Me´xico A study was made of the effects of several monoamine-uptake inhibitors on membrane cur- rents elicited by acetylcholine (ACh-currents) generated by rat neuronal ␣2␤4 and mouse mus- cle nicotinic acetylcholine receptors (AChRs) expressed in Xenopus laevis oocytes. For the two types of receptors the monoamine-uptake inhibitors reduced the ACh-currents albeit to different degrees. The order of inhibitory potency was norfluoxetine Ͼ clomipramine Ͼ inda- traline Ͼ fluoxetine Ͼ imipramine Ͼ zimelidine Ͼ 6-nitro-quipazine Ͼ trazodone for neuronal ␣2␤4 AChRs, and norfluoxetine Ͼ fluoxetine Ͼ imipramine Ͼ clomipramine Ͼ indatraline Ͼ zimelidine Ͼ trazodone Ͼ 6-nitro-quipazine for muscle AChRs. Thus, the most potent inhibitor was norfluoxetine, whilst the weakest ones were trazodone, 6-nitro-quipazine and zimelidine. Effects of the tricyclic antidepressant imipramine were studied in more detail. Imipramine inhibited reversibly and non-competitively the ACh-current with a similar inhibiting potency for both neuronal ␣2␤4 and muscle AChRs. The half-inhibitory concentrations of imipramine were 3.65 ± 0.30 ␮M for neuronal ␣2␤4 and 5.57 ± 0.19 ␮M for muscle receptors. The corre- sponding Hill coefficients were 0.73 and 1.2 respectively.
    [Show full text]