DOCSLIB.ORG

Design, Synthesis, Kinetic Analysis, Molecular Modeling, and Pharmacological Evaluation of Novel Inhibitors of Peptide Amidation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

DESIGN, SYNTHESIS, KINETIC ANALYSIS, MOLECULAR MODELING, AND PHARMACOLOGICAL EVALUATION OF NOVEL INHIBITORS OF PEPTIDE AMIDATION A Thesis Presented to the Academic Faculty by Michael Scott Foster In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy in Chemistry Georgia Institute of Technology December 2008 DESIGN, SYNTHESIS, KINETIC ANALYSIS, MOLECULAR MODELING, AND PHARMACOLOGICAL EVALUATION OF NOVEL INHIBITORS OF PEPTIDE AMIDATION Approved by: Dr. Sheldon W. May Dr. Stanley H. Pollock School of Chemistry and Biochemistry Pharmaceutical Sciences Georgia Institute of Technology Mercer University Dr. James C. Powers Dr. Niren Murthy School of Chemistry and Biochemistry School of Biomedical Engineering Georgia Institute of Technology Georgia Institute of Technology Dr. Nicholas V. Hud Date Approved: August 12, 2008 School of Chemistry and Biochemistry Georgia Institute of Technology For Dr. Sheldon W. May, without whose indefatigable kindness, patience, good humor, and positive attitude, I surely would never have completed this work. For Amanda, whose loyalty, love, and trust throughout these many years have ever been a blessing to me. For Dave, the best brother a person could ask for. And for my mother, who gave me everything. I am sorry you could not be here to share in my success. ACKNOWLEDGEMENTS I give, again, my deepest thanks to Dr. Sheldon May for the opportunity to work alongside him and with his group for these wonderful years. Also, many thanks to Dr. Charlie Oldham for listening to me gripe about ill-conceived software default settings and shoddy instrument engineering without every becoming more than mildly irritated with me. His encyclopedic knowledge of many different scientific and technical fields has been a wonderful benefit to my graduate career. I also wish to thank Dr. Stanley Pollock of Mercer University for allowing me to expand my research horizons into pharmacological studies. Thanks also to the following for various contributions to my knowledge, technique, and my general welfare: Dr. Kristi Burns, Dr. Veronica de Silva, Dr. Jennifer Overcast Lane, Dr. Jeffrey Sunman, Dr. John Bauer, Dr. Michael Kulis, Mr. Jeremy Thompson, Mr. Jacob Lucrezi, Ms. Elizabeth Cowan, and Ms. Maggie Schwab. I also wish to thank the other members of my Thesis Committee, Dr. James Powers, Dr. Nicholas Hud, and Dr. Niren Murthy. I appreciate the personal time that everyone has spent on my behalf. Finally, I would like to thank the National Institutes of Health (NIH) and the National Arthritis Foundation for their generous supports of the work presented herein. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS iv LIST OF TABLES viii LIST OF FIGURES ix LIST OF ABBREVIATIONS xii SUMMARY xiv PART 1: DESIGN, SYNTHESIS, KINETIC ANALYSIS, AND MOLECULAR MODELING OF NOVEL INHIBITORS OF PEPTIDE AMIDATION CHAPTER 1: INTRODUCTION 1 General Introduction 1 PAM Localization and Expression 6 Substrates and Inhibitors 24 PAM Mechanism 45 CHAPTER 2: MATERIALS AND METHODS 59 TNP-D-Tyr-L-Val-Gly 59 TNP-D-Tyr-L-Val-(S)-α-Hydroxy-Gly (TNP-YV(OH)G) 59 N-Ac-(D)-Phe-Acrylate 60 N-Ac-(D)-Phe-OMe 61 N-Ac-(D)-Phe-α-Ketophosphonate 61 Methyl Glyoxylate 62 Methyl-N-Ac-(D)-Phe-Acrylate 63 N-Ac-(D)-Phe-Acrylic Acid 63 N-Ac-(L)-Phe-Acrylate 64 N-Ac-(L)-Phe-OEt 64 N-Ac-(L)-Phe-α-Ketophosphonate 65 Methyl-N-Ac-(L)-Phe-Acrylate 66 N-Ac-(L)-Phe-Acrylic Acid 66 Methyl-4-Phenyl-3-Butenoate 67 Spodoptera Frugiperd Cell Culture 67 Expression of X. Laevis Skin AE-1 68 Enzyme Isolation 68 Standard PAM Activity Assay 70 Dilution Assay 70 Progress Curve Assay 71 v Circular Dichroism Spectroscopy 71 HPLC Chiral Chromatography 72 PAM/Ligand Docking 72 Flexible Alignment 74 CHAPTER 3: RESULTS 75 PAM Isolation 75 Synthesis and Characterization of N-Ac-(L)/(D)-Phe-Acrylate 77 Inactivation Kinetics 84 Dilution Assay 87 Progress Curve Assay 99 PAM/Ligand Docking 126 CHAPTER 4: KINETICS AND MODELING DISCUSSION 164 PART 2: NOVEL INHIBITORS OF SUBSTANCE P 192 BIOACTIVATION AS POTENTIAL ANTI- INFLAMMATORY AND ANTI-NEOPLASTIC AGENTS CHAPTER 5: INTRODUCTION 193 General Introduction 193 Substance P and Neurokinin Expression 199 Protein Kinase C and Downstream Cellular Signaling 201 Nuclear Factor κB (Nuclear Factor κB) 202 Effects of Substance P on Cells of the Immune System 206 Substance P and Apoptosis 213 CHAPTER 6: MATERIALS AND METHODS 217 Animals 217 Reagents 217 Preparation and Administration of PBA and APAA-OMe 218 Collection of Blood/Serum from Sprague/Dawley Rats 218 Analysis of Serum PAM Activity 219 Induction of Adjuvant Arthritis and Carrageenan Edema 219 WB-Neo and WB-Ras Cell Culture and PAM Activity 220 Statistical Analysis 221 CHAPTER 7: RESULTS 222 Effect of PBA on Serum PAM Activity in vivo 224 Effect of N-Ac-(L)-Phe-Acrylate on Serum PAM Activity 226 Effect of Methyl-N-Ac-(L)-Phe-Acrylate on Serum PAM Activity 229 Acute Anti-Inflammatory Effect of APAA-OMe 232 Effect of APAA-OMe on Adjuvant-Induced Polyarthritis (AIP) 235 PAM Activity in WB-Neo Cells and Inhibition by PBA 237 PAM Activity in WB-Ras Cells and Inhibition by PBA 239 vi Cultured WB-Neo and WB-Ras Cells: Inhibition by 240 PBA and PBA-OMe CHAPTER 8: DISCUSSION 243 REFERENCES 261 vii LIST OF TABLES Table 1. Isolation Table of PAM (AE-1) Expressed from Sf9 Cells 76 Table 2. Collected Kinetic Parameters from Dilution and Progress Curve 125 viii LIST OF FIGURES Figure 1. Reaction Scheme for PAM and PGL 25 Figure 2. Structures of Hippuric Acid Analogs 30 Figure 3. Cartoon of the X-Ray Structure of Oxidized PAM 35 Figure 4. Molecular Structures of Compounds Tested 57 Figure 5. Synthetis of N-Ac-Phe-Acrylate 79 Figure 6. Overlaid Circular Dichroism Spectra of N-Ac-(L)-Phe-Acrylate 81 Figure 7. Chromatogram of Methyl-N-Ac-(D)-Phe-Acrylate 82 Figure 8. Chromatogram of Methyl-N-Ac-(L)-Phe-Acrylate 83 Figure 9. Possible Mechanistic Pathways for Mechanism-Based Inactivators 85 Figure 10. Semi-Log Plot of Percent Initial Activity vs. Time ((L)-Phe-Acrylate) 90 Figure 11. Kitz/Wilson Double-Reciprocal Plot (N-Ac-(L)-Phe-Acrylate) 92 Figure 12. Semi-Log Plot of Percent Initial Activity vs. Time ((D)-Phe-Acrylate) 94 Figure 13. Kitz/Wilson Double-Reciprocal Plot (N-Ac-(D)-Phe-Acrylate) 95 Figure 14. Semi-Log Plot of Percent Initial Activity vs. Time ((L)-Met-Acrylate) 98 Figure 15. Kitz/Wilson Double-Reciprocal Plot (N-Ac-(L)-Met-Acrylate) 99 Figure 16. Product Concentration vs. Time (N-Ac-(L)-Phe-Acrylate) 108 Figure 17. Plot of [TNP-YV(OH)G]∞ vs. 1/[N-Ac-(L)-Phe-Acrylate] 109 Figure 18. Plot of 1/slope vs. 1/[TNP-YVG] (N-Ac-(L)-Phe-Acrylate) 110 Figure 19. Plot of 1/kobs vs. 1/[N-Ac-(L)-Phe-Acrylate] 111 Figure 20. Ratio of y-Intercept/Slope vs. [TNP-YVG]/(Km + [TNP-YVG]) 112 Figure 21. Product Concentration vs. Time (N-Ac-(D)-Phe-Acrylate) 113 ix Figure 22. Plot of [TNP-YV(OH)G]∞ vs. 1/[N-Ac-(D)-Phe-Acrylate] 114 Figure 23. Plot of 1/slope vs. 1/[TNP-YVG] (N-Ac-(D)-Phe-Acrylate 115 Figure 24. Plot of 1/kobs vs. 1/[N-Ac-(D)-Phe-Acrylate] 116 Figure 25. Ratio of y-Intercept/Slope vs. [TNP-YVG]/(Km + [TNP-YVG]) 117 Figure 26. Product Concentration vs. Time (N-Ac-(L)-Met-Acrylate) 118 Figure 27. Plot of [TNP-YV(OH)G]∞ vs. 1/[N-Ac-(L)-Met-Acrylate] 119 Figure 28. Plot of 1/slope versus 1/[TNP-YVG] (N-Ac-(L)-Met-Acrylate) 120 Figure 29. Plot of 1/kobs versus 1/[N-Ac-(L)-Met-Acrylate] 121 Figure 30. Ratio of y-Intercept/Slope vs. [TNP-YVG]/(Km + [TNP-YVG]) 122 Figure 31. Hanes-Woolf Plot of [TNP-YVG]/v vs. [TNP-YVG] w/KI 123 Figure 32. Hanes-Woolf Plot of [TNP-YVG]/v vs. [TNP-YVG] w/o KI 124 Figure 33. IYG Docked to PAM Active Site 133 Figure 34. N-Ac-(L)-Phe-Gly Docked to PAM Active Site 136 Figure 35. N-Ac-(D)-Phe-Gly Docked to PAM Active Site 137 Figure 36. N-Ac-(L)-Leu-OCH2-COOH Docked to PAM Active Site 140 Figure 37. N-Ac-(D)-Leu-OCH2-COOH Docked to PAM Active Site 142 Figure 38. N-Ac-(L)-Phenylglycine-Gly Docked to PAM Active Site 144 Figure 39. O-Ac-(R)-Mandelyl-Gly Docked to PAM Active Site 145 Figure 40. N-Ac-(L)-Phe-Acrylate Docked to PAM Active Site 147 Figure 41. N-Ac-(D)-Phe-Acrylate Docked to PAM Active Site 148 Figure 42. N-Ac-(L)-Met-Acrylate Docked to PAM Active Site 151 Figure 43. N-Ac-(D)-Met-Acrylate Docked to PAM Active Site 152 Figure 44. N-Ac-(L)-2’-Thienyl-Acrylate Docked to PAM Active Site 154 x Figure 45. N-Ac-(D)-2’-Thienyl-Acyrlate Docked to PAM Active Site 155 Figure 46. N-Ac-(L)-Phe-Crotonate Docked to PAM Active Site 157 Figure 47. N-Ac-(D)-Phe-Crotonate Docked to PAM Active Site 158 Figure 48. N-Ac-(L)-Phe-Propiolate Docked to PAM Active Site 160 Figure 49. N-Ac-(D)-Phe-Propiolate Docked to PAM Active Site 161 Figure 50. PBA Docked to PAM Active Site 162 Figure 51. Flexible Alignment Overlay of N-Ac-(L)-Phe-Gly and 175 N-Ac-(L)-Phe-Acrylate Figure 52. Flexible Alignment Overlay of N-Ac-(L)-Phe-Gly and 176 N-Ac-(D)-Phe-Gly Figure 53. Flexible Alignment Overlay of N-Ac-(L)-Phe-Gly and 177 N-Ac-(D)-Phe-Acrylate Figure 54.
Recommended publications
  • Sized Neuropeptides

    Sized Neuropeptides

    M ETHODS IN MOLECULAR BIOLOGY™ Series Editor John M. Walker School of Life Sciences University of Hertfordshire Hatfield, Hertfordshire, AL10 9AB, UK For further volumes: http://www.springer.com/series/7651 Neuropeptides Methods and Protocols Edited by Adalberto Merighi Dipartimento di Morfofisiologia Veterinaria, Università degli Studi di Torino, Grugliasco, TO, Italy; Istituto Nazionale di Neuroscienze (INN), Università degli Studi di Torino, Grugliasco, TO, Italy Editor Adalberto Merighi Dipartimento di Morfofisiologia Veterinaria Università degli Studi di Torino and Istituto Nazionale di Neuroscienze (INN) Università degli Studi di Torino Grugliasco, TO, Italy [email protected] Please note that additional material for this book can be downloaded from http://extras.springer.com ISSN 1064-3745 e-ISSN 1940-6029 ISBN 978-1-61779-309-7 e-ISBN 978-1-61779-310-3 DOI 10.1007/978-1-61779-310-3 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011936011 © Springer Science+Business Media, LLC 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.
  • Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

    Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

    Molecular Pharmacology Fast Forward. Published on June 2, 2020 as DOI: 10.1124/mol.120.119388 This article has not been copyedited and formatted. The final version may differ from this version. File name: Opioid peptides v45 Date: 5/28/20 Review for Mol Pharm Special Issue celebrating 50 years of INRC Five decades of research on opioid peptides: Current knowledge and unanswered questions Lloyd D. Fricker1, Elyssa B. Margolis2, Ivone Gomes3, Lakshmi A. Devi3 1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; E-mail: [email protected] 2Department of Neurology, UCSF Weill Institute for Neurosciences, 675 Nelson Rising Lane, San Francisco, CA 94143, USA; E-mail: [email protected] 3Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, Annenberg Downloaded from Building, One Gustave L. Levy Place, New York, NY 10029, USA; E-mail: [email protected] Running Title: Opioid peptides molpharm.aspetjournals.org Contact info for corresponding author(s): Lloyd Fricker, Ph.D. Department of Molecular Pharmacology Albert Einstein College of Medicine 1300 Morris Park Ave Bronx, NY 10461 Office: 718-430-4225 FAX: 718-430-8922 at ASPET Journals on October 1, 2021 Email: [email protected] Footnotes: The writing of the manuscript was funded in part by NIH grants DA008863 and NS026880 (to LAD) and AA026609 (to EBM). List of nonstandard abbreviations: ACTH Adrenocorticotrophic hormone AgRP Agouti-related peptide (AgRP) α-MSH Alpha-melanocyte stimulating hormone CART Cocaine- and amphetamine-regulated transcript CLIP Corticotropin-like intermediate lobe peptide DAMGO D-Ala2, N-MePhe4, Gly-ol]-enkephalin DOR Delta opioid receptor DPDPE [D-Pen2,D- Pen5]-enkephalin KOR Kappa opioid receptor MOR Mu opioid receptor PDYN Prodynorphin PENK Proenkephalin PET Positron-emission tomography PNOC Pronociceptin POMC Proopiomelanocortin 1 Molecular Pharmacology Fast Forward.
  • BAM8-22 and Its Receptor MRGPRX1 May Attribute to Cholestatic Pruritus

    BAM8-22 and Its Receptor MRGPRX1 May Attribute to Cholestatic Pruritus

    www.nature.com/scientificreports OPEN BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus Received: 10 April 2019 Babina Sanjel1,2, Han-Joo Maeng1,2 & Won-Sik Shim 1,2 Accepted: 11 July 2019 Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we Published: xx xx xxxx show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was signifcantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was signifcantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confrmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid signifcantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons. Cholestasis, characterized by decreased bile fow, occurs due to impaired bile secretion from hepatocytes or obstruction of intra- or extrahepatic bile ducts. Generally, cholestasis is accompanied by typical symptoms such as increased accumulation of bile acids in circulation, jaundice, dark urine, and steatorrhea.
  • The Atypical Chemokine Receptor ACKR3/CXCR7 Is a Broad-Spectrum Scavenger for Opioid Peptides

    The Atypical Chemokine Receptor ACKR3/CXCR7 Is a Broad-Spectrum Scavenger for Opioid Peptides

    University of Southern Denmark The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides Meyrath, Max; Szpakowska, Martyna; Zeiner, Julian; Massotte, Laurent; Merz, Myriam P.; Benkel, Tobias; Simon, Katharina; Ohnmacht, Jochen; Turner, Jonathan D.; Krüger, Rejko; Seutin, Vincent; Ollert, Markus; Kostenis, Evi; Chevigné, Andy Published in: Nature Communications DOI: 10.1038/s41467-020-16664-0 Publication date: 2020 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Meyrath, M., Szpakowska, M., Zeiner, J., Massotte, L., Merz, M. P., Benkel, T., Simon, K., Ohnmacht, J., Turner, J. D., Krüger, R., Seutin, V., Ollert, M., Kostenis, E., & Chevigné, A. (2020). The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nature Communications, 11, [3033]. https://doi.org/10.1038/s41467-020-16664-0 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 05. Oct. 2021 ARTICLE https://doi.org/10.1038/s41467-020-16664-0 OPEN The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides Max Meyrath1,9, Martyna Szpakowska 1,9, Julian Zeiner2, Laurent Massotte3, Myriam P.
  • Opioid Peptides: Medicinal Chemistry, 69

    Opioid Peptides: Medicinal Chemistry, 69

    Opioid Peptides: Medicinal Chemistry DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Opioid Peptides: Medicinal Chemistry Editors: Rao S. Rapaka, Ph.D. Gene Barnett, Ph.D. Richard L. Hawks, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 69 1986 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. SIDNEY COHEN, M.D. Temple University School of Medicine Los Angeles, California Philadelphia, Pennsylvania SYDNEY ARCHER, Ph.D. MARY L. JACOBSON Rensselaer Polytechnic lnstitute National Federation of Parents for Troy, New York Drug Free Youth RICHARD E. BELLEVILLE, Ph.D. Omaha, Nebraska NB Associates, Health Sciences Rockville, Maryland REESE T. JONES, M.D. KARST J. BESTEMAN Langley Porter Neuropsychiatric lnstitute San Francisco, California Alcohol and Drug Problems Association of North America WashIngton, DC DENISE KANDEL, Ph.D. GILBERT J. BOTVIN, Ph.D. College of Physicians and Surgeons of Cornell University Medical College Columbia University New York, New York New York, New York JOSEPH V.
  • Proenkephalin System in Human Polymorphonuclear Cells

    Proenkephalin System in Human Polymorphonuclear Cells

    Proenkephalin system in human polymorphonuclear cells. Production and release of a novel 1.0-kD peptide derived from synenkephalin. O Vindrola, … , S Finkielman, V Nahmod J Clin Invest. 1990;86(2):531-537. https://doi.org/10.1172/JCI114740. Research Article In the hematopoietic system a pluripotent stem cell generates precursors for lymphoid and myeloid lineages. Proenkephalin-derived peptides were previously detected in differentiated lymphoid cells. We have studied whether the proenkephalin system is expressed in a typical differentiated cell of the myeloid lineage, the neutrophil. Human peripheral polymorphonuclear cells contain and release proenkephalin-derived peptides. The opioid portion of proenkephalin (met- enkephalin-containing peptides) was incompletely processed, resulting in the absence of low molecular weight products. The nonopioid synenkephalin (proenkephalin 1-70) molecule was completely processed to a 1.0-kD peptide derived from the COOH-terminal. This molecule was characterized in neutrophils by biochemical and immunocytochemical methods. The chemotactic peptide FMLP and the calcium ionophore A23187 induced the release of the proenkephalin-derived peptides, and this effect was potentiated by cytochalasin B. The materials secreted were similar to those present in the cell, although in the supernatant a higher proportion corresponded to more processed products. The 1.0-kD peptide was detected in human, bovine, and rat neutrophils, but the chromatographic pattern of synenkephalin-derived peptides suggests a differential posttranslational processing among species. These findings demonstrate the existence of the proenkephalin system in human neutrophils and the production and release of a novel 1.0-kD peptide derived from the synenkephalin molecule. The presence of opioid peptides in neutrophils suggests their participation in the inflammatory process, including a local analgesic effect.
  • Information to Users

    Information to Users

    The direct and modulatory antinociceptive actions of endogenous and exogenous opioid delta agonists Item Type text; Dissertation-Reproduction (electronic) Authors Vanderah, Todd William. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 11/10/2021 07:59:52 Link to Item http://hdl.handle.net/10150/187190 INFORMATION TO USERS This ~uscript }las been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely. event that the author did not send UMI a complete mannscript and there are missing pages, these will be noted Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginnjng at the upper left-hand comer and contimJing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy.
  • List of Psychoactive Drug Spirits for MD A-Methylfentanyl, Abilify

    List of Psychoactive Drug Spirits for MD A-Methylfentanyl, Abilify

    List of Psychoactive Drug Spirits for MD A-Methylfentanyl, Abilify, abnormal basal ganglia function, abuse of medicines, Aceperone, Acepromazine, Aceprometazine, Acetildenafil, Aceto phenazine, Acetoxy Dipt, Acetyl morphone, Acetyl propionyl morphine, Acetyl psilocin, Activation syndrome, acute anxiety, acute hypertension, acute panic attacks, Adderall, Addictions to drugs, Addictions to medicines, Addictions to substances, Adrenorphin, Adverse effects of psychoactive drugs, adverse reactions to medicines, aggression, aggressive, aggressiveness, agitated depression, Agitation and restlessness, Aildenafil, Akuammine, alcohol abuse, alcohol addiction, alcohol withdrawl, alcohol-related brain damage, alcohol- related liver damage, alcohol mix with medicines for adverse reaction, Alcoholism, Alfetamine, Alimemazine, Alizapride, Alkyl nitrites, allergic breathing reactions to meds, choking to anaphallectic shock, & death; allergic skin reactions to meds, rash, itchyness, hives, welts, etc, Alletorphine, Almorexant, Alnespirone, Alpha Ethyltryptamine, Alpha Neoendorphin, alterations in brain hormones, alterations in mental status, altered consciousness, altered mind, Altoqualine, Alvimopan, Ambien, Amidephrine, Amidorphin, Amiflamine, Amisulpride, Amphetamines, Amyl nitrite, Anafranil, Analeptic, Anastrozole, Anazocine, Anilopam, Antabuse, anti anxiety meds, anti dopaminergic activity, anti seizure meds, Anti convulsants, Anti depressants, Anti emetics, Anti histamines, anti manic meds, anti parkinsonics, Anti psychotics, Anxiety disorders,
  • BMA BIOMEDICALS Peninsula Laboratories

    BMA BIOMEDICALS Peninsula Laboratories

    BMA BIOMEDICALS Peninsula Laboratories T-4521 Rabbit anti Peptide F (Prepro-Enkephalin A) (104-137) (bovine) Proenkephalin, also known as proenkephalin A, is an endogenous opioid polypeptide hormone which, via proteolyic cleavage, produces the enkephalin peptides [Met]enkephalin, and to a lesser extent, [Leu]enkephalin. The pre-proenkephalin gene contains four copies of Met-enkephalin and one copy each of Leu-enkephalin, the heptapeptide Met-enkephalin-Arg- Phe, and the octapeptide Met-Enkephalin-Arg-Gly-Leu. Other endogenous opioid peptides produced by proenkephalin include adrenorphin, amidorphin, BAM-18, BAM-20P, BAM-22P, peptide B, peptide E, and peptide F. Peptide F contains [Met5]enkephalin sequences at both its N terminus and its C terminus. The carboxy-terminally amidated peptide comprising the first 26 amino acids of peptide F is named amidorphin. This antibody was generated by immunization of rabbits with Peptide F coupled to a carrier protein. TECHNICAL AND ANALYTICAL CHARACTERISTICS Lot number: A04004 Host species: Rabbit IgG Quantity: 50µl Format: Neat undiluted antiserum, lyophilized, packaged under nitrogen. Reconstitute by adding 50µl distilled water. This will give the equivalent of undiluted antiserum. Stability: Original vial: at least one year at 4º - 8ºC from date of delivery. Minimize repeated thawing and freezing of the antiserum by freezing aliquots at - 20ºC or below. Applications: This antibody has been tested and validated in ELISA against Peptide F. Other applications like immunohistochemistry (IHC), FACS or Western Blot may work as well. Optimal dilutions should be determined by the end user. Please see www.bma.ch for protocols and general information. Immunogen: Synthetic peptide H-Tyr-Gly-Gly-Phe-Met-Lys-Lys-Met-Asp-Glu-Leu-Tyr- Pro-Leu-Glu-Val-Glu-Glu-Glu-Ala-Asn-Gly-Gly-Glu-Val-Leu-Gly-Lys-Arg- Tyr-Gly-Gly-Phe-Met-OH coupled to carrier protein.
  • Quality Control Record Opioid Peptide Library

    Quality Control Record Opioid Peptide Library

    Quality Control Record Opioid Peptide Library Catalog No. L‐002 Well # Position* Catalog # Product Name M.W. PLATE I 1I‐A‐2 021‐01 Dynorphin, big (Human, Rat, Mouse, Porcine) 3982.26 2I‐A‐3 021‐03 Dynorphin A (Human, Rat, Mouse, Porcine) 2147.51 3I‐A‐4 021‐08 Dynorphin A (1‐6) / Endorphin (1‐6), alpha‐Neo / Leu‐Enkephalin‐Arg (Human, Rat, Mouse, Porcine) 711.38 4I‐A‐5 021‐21 Dynorphin A (1‐13) (Human, Rat, Mouse, Porcine) 1602.99 5I‐A‐6 021‐24 Dynorphin A (2‐13) amide (Human, Rat, Mouse, Porcine) 1439.82 6I‐A‐7 021‐30 Dynorphin A (2‐17) (Human, Rat, Mouse, Porcine) 1983.14 7I‐A‐8 021‐37 Dynorphin B / Rimorphin (Human, Rat, Mouse, Porcine) 1570.86 8I‐A‐9 021‐40 Endorphin, alpha‐Neo (Porcine) 1228.46 9I‐A‐10 021‐44 Endorphin, beta‐neo 1099.59 10 I‐A‐11 021‐55 Orphanin FQ / Nociceptin (Human, Rat, Mouse, Ox) 1809.06 11 I‐B‐2 021‐58 pro‐Orphanin FQ (85‐119) / pro‐Nociceptin (85‐119) / Nocistatin‐35 (Rat) 3907.25 12 I‐B‐3 021‐59 pro‐Orphanin FQ (141‐157) / pro‐Nociceptin (141‐157) 2081.4 13 I‐B‐4 021‐70 [Phe‐psi‐Gly]‐Orphanin FQ (1‐13) amide / [Phe‐psi‐Gly]‐Nociceptin (1‐13) amide (Human, Rat, Mouse, Ox) 1376.6 14 I‐B‐5 021‐71 Orphanin FQ (1‐13) amide / Nociceptin (1‐13) amide (Human, Rat, Mouse, Ox) 1381.6 15 I‐B‐6 021‐75 prepro‐Orphanin FQ (111‐127) / Nocistatin / PNP‐3 (Bovine) 1927.1 16 I‐B‐7 021‐78 prepro‐Orphanin FQ (98‐127) / Nocistatin‐30 (Human) 3561.98 17 I‐B‐8 021‐80 PNP‐3‐8P (Bovine) 1015.13 18 I‐B‐9 021‐81 PNP‐2/3 / Nocistatin‐41 (Mouse) 4375.71 19 I‐B‐10 021‐85 prepro‐Orphanin FQ (154‐181), free acid (Rat) / prepro‐Orphanin FQ
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0018530 A1 Miao Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2015/0018530 A1 Miao Et Al

    US 201500 18530A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0018530 A1 Miao et al. (43) Pub. Date: Jan. 15, 2015 (54) NOVEL PRODRUG CONTAINING Related U.S. Application Data MOLECULE COMPOSITIONS AND THEIR (60) Provisional application No. 61/605,072, filed on Feb. USES 29, 2012, provisional application No. 61/656,981, (71) Applicant: Ambrx, Inc., La Jolla, CA (US) filed on Jun. 7, 2012. (72) Inventors: Zhenwei Miao, San Diego, CA (US); Publication Classification Ho Sung Cho, San Diego, CA (US); Bruce E. Kimmel, Leesburg, VA (US) (51) Int. Cl. A647/48 (2006.01) (73) Assignee: AMBRX, INC., La Jolla, CA (US) C07K 6/28 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/381,196 CPC ....... A6IK 47/48715 (2013.01); C07K 16/2896 (2013.01); A61K 47/48215 (2013.01); A61 K (22) PCT Fled: Feb. 28, 2013 47/48284 (2013.01); A61K 47/48384 (2013.01) USPC ....................................................... 530/387.3 (86) PCT NO.: PCT/US2O13/028332 S371 (c)(1), (57) ABSTRACT (2) Date: Aug. 26, 2014 Novel prodrug compositions and uses thereof are provided. Patent Application Publication Jan. 15, 2015 Sheet 1 of 21 US 201S/0018530 A1 FIGURE 1. Antigen recognition site Hinge Peptide Patent Application Publication Jan. 15, 2015 Sheet 2 of 21 US 2015/0018530 A1 FIGURE 2 M C7 leader VH(108) (GGGGS)4 VL(108) Y96xs His A. ( +PEG ) His 144 Tyr190 Lys248 Ser136am (+PEG) Leu156 B. 6X His VH(108) (GGGGS)4 VL(108) H, is Leu156 g3 ST lear VL (108) Ck(hu) VH(108) CH1(hu) 6X His - SD L I (AA SP re A Lys 142 am Thr204 am Lys219 am Patent Application Publication Jan.
  • Supplementary Materials: AGTR1 Is Overexpressed in Neuroendocrine

    Supplementary Materials: AGTR1 Is Overexpressed in Neuroendocrine

    Supplementary Materials: AGTR1 Is Overexpressed in Neuroendocrine Neoplasms, Regulates Secretion and May Potentially Serve as a Target for Molecular Imaging and Therapy Samantha Exner, Claudia Schuldt, Sachindra Sachindra, Jing Du, Isabelle Heing-Becker, Kai Licha, Bertram Wiedenmann and Carsten Grötzinger Table S1. Screening library compound list.