DOCSLIB.ORG

The Immunomodulation of Dynorphin 1-17 and Its Biotransformation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Immunomodulation of Dynorphin 1-17 and Its Biotransformation The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways Siti Sarah Fazalul Rahiman BPharm (Hons), MSc (Immunopharmacology) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2017 School of Pharmacy i Abstract Inflammation is a complex physiological process that involves host defense mechanisms in response to the intrusion of harmful external stimuli. Uncoordinated inflammatory responses, however, are the underlying pathophysiological cause of many chronic diseases. Inflammation is characterised by the burgeoning migration of leukocytes to the point of injury and subsequent release of pro-nociceptive mediators, generating inflammatory pain. Dynorphin 1-17 (DYN 1-17) is endogenously produced and released from leukocytes upon stimulation by local inflammatory factors in the inflamed area. This opioid peptide primarily binds to kappa-opioid receptor (KOR) to produce analgesia. Under inflammatory milieu, DYN 1-17 undergoes spontaneous degradation, yielding a variety of opioid and non-opioid fragments that may have significant implications in inflammation. The underlying cellular effects of these fragments remain unclear. This thesis seeks to explore potential mechanistic insights into selected major DYN 1-17 fragments, identified from a previous biotransformation study of DYN 1-17 in rodent inflamed tissue. This thesis examines the DYN 1-17 fragments modulation of intracellular signals associated with inflammation and thereby, gain an insight into novel therapeutic targets through exploring these endogenous mechanisms. Utilising THP-1 macrophages as an in vitro model of inflammation, this thesis begins with a semi- quantitative assessment of nuclear factor-kappa B/p65 (NF-κB/p65) translocation, a major transcription factor that regulates genes responsible for immune and inflammatory responses. The findings presented in Chapter Three of this thesis demonstrated that DYN 1-17 and selected major fragments (DYN 1-6, 1-7, 1-9, 1-10, 1-11, 3-14, 6-12, 2-17 and 7-17) significantly attenuated NF- κB/p65 nuclear translocation induced by lipopolysaccharide (LPS), with the greatest reduction observed with DYN 1-7 at 10 nM. A selective KOR antagonist, ML-190, was used to examine KOR involvement in this inhibitory action. ML-190 significantly reversed the inhibition of NF- κB/p65 translocation produced by DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not DYN 1-10 and DYN 1-11. Cytokine production is linked as a downstream process to NF-κB activation; hence it is necessary to evaluate the ability of DYN 1-17 and selected biotransformation fragments in the modulation of IL- 1β and TNF-α release in differentiated THP-1 cells, as presented in Chapter Four, to gain an insight into the effects on major pro-inflammatory cytokines. DYN 1-17 and the fragments, demonstrated differential modulatory effects on LPS-induced release of IL-1β and TNF-α. DYN 1-7 and DYN 1- 6, inhibited and elevated the secretion of both cytokines, respectively, in a concentration-dependent manner (10-11 to 10-7 M). DYN 1-17, however, only inhibited IL-1β release from differentiated ii THP-1 cells and had no effect on TNF-α secretion. Intriguingly, DYN 3-14 at 10-17 to 10-11 M demonstrated significant inhibition on IL-1β release and paradoxically increased TNF-α levels at 10-11 to 10-7 M. Subsequent antagonism with ML-190 only reversed the effects produced by DYN 1-17, DYN 1-6 and DYN 1-7 on IL-1β release at 10-7 M, 10-9 M and 10-11 M, respectively. Likewise, the effects of DYN 1-6 (10-7 M) and DYN 1-7 (10-11 M and 10-9 M) on TNF-α release were also blocked by ML-190. Taken together, the findings from Chapter Three and Four, collectively demonstrated that DYN 1-17 and a select of biotransformation fragments involve in the regulation of inflammatory response through inhibition of NF-κB/p65 translocation and modulation of cytokine release via KOR-dependent and -independent pathways. Chapter Five of this thesis investigates the effects of DYN 1-17 and selected biotransformation fragments at the Toll-like receptor 4 (TLR4), implicated in LPS-induced activation of NF-κB signaling pathway. Of these fragments, only DYN 3-14 showed significant concentration-dependent attenuation on TLR4 activation in HEK-Blue™-hTLR4 cells, albeit 300-fold lower than LPS-RS, a potent TLR4 antagonist. This result thus describes a potential role for DYN 3-14 as an antagonist at TLR4, and as a consequence, highlights its involvement in regulating inflammatory signals through a non-opioid mechanism. In conjunction with the immunomodulatory effects seen in select fragments of DYN 1-17, Chapter Six of this thesis aims to extend previous findings of DYN 1-17 biotransformation study in rodent inflamed tissues, by further characterising the degradation of DYN 1-17 in the context of human inflammatory disease, chronic rhinosinusitis (CRS). Data obtained by LC-MS analysis revealed a similar range of fragments in inflamed human nasal tissue homogenates from those found in incubations with rodent inflamed paw tissues. Intriguingly, DYN 3-14 and DYN 1-5 were the major hydrolysis fragments produced until the end of the incubation period, suggesting that these fragments may possess important roles in the immunoregulation and therefore, may be useful as potential therapeutic agents for the treatment CRS. In conclusion, the findings presented within this thesis collectively highlight the pharmacological differences that exist between DYN 1-17 and its biotransformation fragments on inflammatory signalling pathways, through opioid- and non-opioid-dependent pathways. Furthermore, this thesis postulates that the effects of DYN 1-17 in inflammation may not be solely dependent on the parent molecule, but may also be attributed to the modulatory effects of other major biotransformation fragments. iii Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. iv Publications during candidature Peer reviewed papers: Fazalul Rahiman SS, Morgan M, Gray P, Shaw PN, Cabot PJ. Dynorphin 1-17 and its N-terminal biotransformation fragments modulate lipopolysaccharide-stimulated nuclear factor-kappaB nuclear translocation, interleukin-1beta and tumour necrosis factor-alpha in differentiated THP-1 cells. PLoS One. 2016;11(4):e0153005. Rahiman SS, Morgan M, Gray P, Shaw PN, Cabot PJ. Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway. Peptides. 2017;90:48-54. Conference abstracts: Fazalul Rahiman, SS, Morgan, M, Gray, P, Shaw, PN & Cabot, PJ. Peripheral kappa opioid receptors (KOR) stimulation exerts anti-inflammatory effects in lipopolysaccharide (LPS)-activated macrophages. Conference: International Congress of Immunology (ICI); 2016, Melbourne, Australia. Eur. J. Immunol. 2016. 46, S1, page 399. Meeting Abstract number 337 Fazalul Rahiman, SS, Morgan, M, Gray, P, Shaw, PN & Cabot, PJ. Dynorphin 1-17 and its biotransformation fragments modulate lipopolysaccharide (LPS)-induced release of interleukin- 1beta and tumour necrosis factor-alpha in differentiated THP-1 cells. Conference: APSA-ASCEPT Joint Scientific Meeting; 2015, Hobart, Australia. Abstract 538. Fazalul Rahiman, SS, Morgan, M, Gray, P, Shaw, PN & Cabot, PJ. Effect of Dynorphin A fragments on translocation of nuclear factor-kappa B (NF-κB) in THP-1 cell-derived macrophages. Conference: Australian Pain Society (APS) 35th Annual Scientific Meeting; 2015, Brisbane, Australia. Anaesthesia and Intensive Care, 43(3), page 380-411 (abstract 39) Fazalul Rahiman, SS, Morgan, M, Gray, P, Shaw, PN & Cabot, PJ. Biotransformed dynorphin A fragments attenuate lipopolysaccharide-stimulated activation of THP-1 cell-derived macrophages through inhibition on nuclear factor-kappaB (NF-κB) translocation. Conference: ASCEPT- MPGPCR Joint Scientific Meeting; 2014, Melbourne, Australia. Abstract P608. v Publications included in this thesis No publications. vi Contributions by others to the thesis The work presented in this thesis was conceived, designed, and conducted by me, with contributions by many others. My advisory team members consisting of Assoc. Prof Peter John Cabot, Prof Paul Nicholas Shaw, Dr Michael Morgan and Dr Paul Gray jointly contributed to the intellectual concepts of the project, manuscripts preparation for publication and thesis write-up, where relevant. The immortalised THP- 1 cell line was a kind gift from Assoc. Prof Marie-Odile Parat, School of Pharmacy, The University of Queensland. The PMA-differentiated THP-1 cells model, utilised in Chapter 3 and 4 of this thesis was developed by others and adapted in our laboratory by Dr Michael Morgan.
Load more

Recommended publications
  • Genscript Product Catalog 2013-2014 Genscript Product Catalog
    GenScript Product Catalog 2013-2014 GenScript Product Catalog www.genscript.com GenScript USA Inc. 860 Centennial Ave. Piscataway, NJ 08854USA Tel: 1-732-885-9188 / 1-732-885-9688 Toll-Free Tel: 1-877-436-7274 Fax: 1-732-210-0262 / 1-732-885-5878 Email: [email protected] Nucleic Acid Purification and Analysis Business Development Tel: 1-732-317-5088 PCR PCR and Cloning Email: [email protected] Protein Analysis Antibodies 2013-2014 Peptides Welcome to GenScript GenScript USA Incorporation, founded in 2002, is a fast-growing biotechnology company and contract research organization (CRO) specialized in custom services and consumable products for academic and pharmaceutical research. Built on our assembly-line mode, one-stop solutions, continuous improvement, and stringent IP protection, GenScript provides a comprehensive portfolio of products and services at the most competitive prices in the industry to meet your research needs every day. Over the years, GenScript’s scientists have developed many innovative technologies that allow us to maintain our position at the cutting edge of biological and medical research while offering cost-effective solutions for customers to accelerate their research. Our advanced expertise includes proprietary technology for custom gene synthesis, OptimumGeneTM codon optimization technology, CloneEZ® seamless cloning technology, FlexPeptideTM technology for custom peptide synthesis, BacPowerTM technology for protein expression and purification, T-MaxTM adjuvant and advanced nanotechnology for custom antibody production, as well as our ONE-HOUR WesternTM detection system and eStain® protein staining system. GenScript offers a broad range of reagents, optimized kits, and system solutions to help you unravel the mysteries of biology. We also provide a comprehensive portfolio of customized services that include Bio-Reagent, Bio-Assay, Lead Optimization, and Antibody Drug Development which can be effectively integrated into your value chain and your operations.
    [Show full text]
  • Biological Redundancy of Endogenous GPCR Ligands in the Gut and the Potential for Endogenous Functional Selectivity
    REVIEW ARTICLE published: 28 November 2014 doi: 10.3389/fphar.2014.00262 Biological redundancy of endogenous GPCR ligands in the gut and the potential for endogenous functional selectivity Georgina L. Thompson1, Meritxell Canals1 and Daniel P.Poole1,2 * 1 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia 2 Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia Edited by: This review focuses on the existence and function of multiple endogenous agonists Dominique Massotte, Institut des of the somatostatin and opioid receptors with an emphasis on their expression in the Neurosciences Cellulaires et Intégratives, France gastrointestinal tract. These agonists generally arise from the proteolytic cleavage of prepropeptides during peptide maturation or from degradation of peptides by extracellular Reviewed by: Jakub Fichna, Medical University of or intracellular endopeptidases. In other examples, endogenous peptide agonists for the Lodz, Poland same G protein-coupled receptors can be products of distinct genes but contain high Pamela J. Hornby, Johnson & sequence homology. This apparent biological redundancy has recently been challenged Johnson, USA by the realization that different ligands may engender distinct receptor conformations *Correspondence: linked to different intracellular signaling profiles and, as such the existence of distinct Daniel P.Poole, Drug Discovery Biology, Monash Institute of ligands may underlie mechanisms to finely tune physiological responses. We propose that Pharmaceutical Sciences, 381 Royal further characterization of signaling pathways activated by these endogenous ligands will Parade, Parkville, VIC 3052, Australia provide invaluable insight into the mechanisms governing biased agonism. Moreover, these e-mail: [email protected] ligands may prove useful in the design of novel therapeutic tools to target distinct signaling pathways, thereby favoring desirable effects and limiting detrimental on-target effects.
    [Show full text]
  • Part 7. Indexes
    Peptide Sequences Index Part 7. Indexes Index A. Peptide Sequences White & White - Proteins, Peptides & Amino Acids SourceBook 975 Peptide Sequences Index Ala-Ala-Pro-Lys . 218 A Ala-Ala-Pro-Met . 218 Ala-Ala-Pro-Nle . 218 Abu-Ala· 208 Ala-Ala-Pro-Nva . 218 Abu-Arg . 208, 740 Ala-Ala-Pro-Orn • 218 Abu-Asn-Arg-Leu-Glu-Ala-Ser-Ser-Arg-Ser-Ser-Lys . 208 Ala-Ala-Pro-Phe . 209, 218, 219, 385 Abu-Gly . 208, 369 Ala-Ala-Pro-Val . 217, 219, 220 Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr· 208 Ala-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr . 220 Abu-Ser-Gln-Asn-Tyr-Pro-lie-Val-Gin· 208 Ala-Ala-Trp-Phe-Lys· 220 Abz-Ala-Ala-Phe-Phe . 208 Ala-Ala-Trp-Phe-Pro-pro-Nle . 220 Abz-Ala-Arg-Val-Nle-Phe-Glu-Ala-Nle . 208 Ala-Ala-Tyr . 221 Abz-Ala-Gly-Leu-Ala . 208 Ala-Ala-Tyr-Ala . 221 Abz-Ala-Phe-Ala-Phe-Asp-Val-Phe-Tyr-Asp . 209 Ala-Ala-Tyr-Ala-Ala . 221 Abz-Arg-Val-Lys-Arg-Gly-Leu-Ala-Tyr-Asp . 209 Ala-Ala-Val· 221, 222 Abz-Arg-Val-Nle-Phe-Glu-Ala-Nle . 209 Ala-Ala-Val-Ala • 221, 222 Abz-Gln-Val-Val-Ala-Gly-Ala . 209 Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu- Abz-Glu-Thr-Leu-Phe-Gln-Gly-Pro-Val-Phe . 209 Ala-Pro-Asp-Glu-Val-Asp . 221 Abz-Gly . 209, 385 Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu­ Abz-Gly-Ala-Ala-Pro-Phe-Tyr-Asp .
    [Show full text]
  • Usbiological Datasheet
    PENK (Proenkephalin-A, PENK) Catalog number 224959 Supplier United States Biological The Proenkephalin precursor proteins are secreted proteins belonging to the opioid neuropeptide precursor family. The proenkephalin proteins are proteolytically processed to form active secreted opioid peptides which function as ligands for the κ-type of opiod receptor. Proenkephalin A precursor contains Synenkephalin, Leu-enkephalin and Met-enkephalin processed active peptides while the Proenkephalin B precursor contains beta-neoendorphin, Dynorphin, Leumorphin, Leu-enkephalin and Rimorphin processed active peptides. beta-endorphin and Met-enkephalin are endogenous opiates while ACTH is crucial for adrenal gland stimulation to release cortisol. MSH increases Melanin production in melanocytes which leads to an increase in skin pigmentation. Leumorphin may be important in apoptosis prevention by being involved in the MAP-K and PI 3-K pathways. Applications Suitable for use in Western Blot, Immunohistochemistry. Other applications not tested. Recommended Dilution Western Blot: 1:500-1:2000 Immunohistochemistry: 1:50-1:200 Optimal dilutions to be determined by the researcher. Storage and Stability May be stored at 4°C for short-term only. Aliquot to avoid repeated freezing and thawing. Store at -20°C. Aliquots are stable for 12 months after receipt. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Immunogen Recombinant full length Human PENK. Formulation Supplied as a liquid PBS, 0.1% sodium azide, 50% glycerol. Purity Purified by immunoaffinity chromatography. Specificity Recognizes endogenous levels of PENK. Species Crossreactivity: Human Product Type Pab Source human Isotype IgG Grade Affinity Purified Applications IHC WB Crossreactivity Hu Storage -20°C MW 31 Powered by TCPDF (www.tcpdf.org).
    [Show full text]
  • 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.
    [Show full text]
  • Synthesis and Biological Evaluation of Dynorphin a Analogues As
    AN ABSTRACT OF THE THESIS OF Heekyung Choi for the degree of Doctor of Philosophy in Pharmacy presented on January 10. 1995. Title: Synthesis and Biological Evaluation of Dynorphin A Analogues as Pharmacological Probes of Opioid Receptors. Redacted for Privacy Abstract approved: Jane V. Aldrich, Ph.D. This research involves the preparation of several series of analogues of the opioid peptide dynorphin A (Dyn A) as pharmacological probes of opioid receptors. The peptides were prepared by using Fmoc-solid phase synthesis on either a hydroxymethylphenoxyacetic acid support or a PAL® (Peptide Amide Linker) resin. Biological activity was evaluated by determining binding affinity at opioid receptors L, K, (5) and by measuring opioid activity in the electrically stimulated guinea pig ileum (GPI). As a part of the investigation of the structure-activity relationships of Dyn A, a series of Trp-containing Dyn A-(1-13) analogues were synthesized. During the preparation, significant amounts of side products were identified as derivatives in which Trp was modified. Further studies found that protection of the indole nitrogen of Trp by Boc was the most effective method to suppress the Trp-modification side reaction during acidic cleavage, as compared to cleavage of the peptide without TT protection by various combinations of scavengers (Chapter 4). In the second project, modification of the "message" sequence in [Trp4]Dyn A-(1-13) by replacing Gly2 with various amino acids and their stereoisomers led to changes in opioid receptor affinity and opioid activity. This result may be due to alteration of the conformation of the peptide, in particular the relative orientation of the aromatic residues (Tyr' and Trp4) which are important for opioid activity (Chapter 5).
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont Et Al
    US 2008O124279A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0124279 A1 Andremont et al. (43) Pub. Date: May 29, 2008 (54) COLONIC DELIVERY USING ZN/PECTIN (52) U.S. Cl. .......................................... 424/9.1; 424/493 BEADS WITH AEUDRAGT COATING (76) Inventors: Antoine Andremont, Malakoff (FR); Helene Huguet, Paris (FR) (57) ABSTRACT Correspondence Address: Drug delivery systems that can deliver therapeutic and/or INTELLECTUAL PROPERTY f TECHNOLOGY diagnostic agents to the colon are disclosed. The systems LAW include pectin beads crosslinked with Zinc or any divalent PO BOX 14329 cation of interest, which beads are then coated with RESEARCH TRIANGLE PARK, NC 27709 Eudragit R-type polymers. The drug delivery systems are orally administrable, but can deliver the active agents to the (21) Appl. No.: 11/985.465 colon. In some embodiments, they can administer the agents to various positions in the gastro-intestinal tract, including the (22) Filed: Nov. 15, 2007 colon. The agent can be a small molecule, peptide, protein, nucleic acid, or complex structures of natural, recombinant or Related U.S. Application Data synthetic origin. In still other embodiments, the agent is a diagnostic agent. The agents can be used to diagnose, treat or (60) Provisional application No. 60/859,600, filed on Nov. investigate humans and animals for a variety of conditions, 17, 2006. including infectious diseases, inflammatory diseases, cancers O O and the like. Colon-specific delivery is obtained by formulat Publication Classification ing a prophylactic, therapeutic, and/or diagnostic agent with (51) Int. Cl. specific polymers that degrade in the colon, Such as pectin.
    [Show full text]
  • 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,
    [Show full text]
  • Prodynorphin-Derived Peptide Expression in Primate Cortex and Striatum
    Neuropeptides (1994) 21, 211-284 $:I Longman Group Ltd 1994 Prodynorphin-derived Peptide Expression in Primate Cortex and Striatum D. J. HEALY and J. H. MEADOR-WOODRUFF Department of Psychiatry, Mental Health Research institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA (Reprint requests to DJH) Abstract-The distributions of four prodynorphin-derived peptides, dynorphin A (l-171, dynorphin A (I-81, dynorphin B, and cr-neo-endorphin were determined in 10 cortical regions and the striatum of the old world monkey (Macaca nemestrina). a-neo-endorphin was the most abundant peptide in both cortex and striatum. The concentrations of all four peptides were significantly greater in the striatum compared to the cortex. In general, concentrations of each peptide tended to be higher in allocortex than in neocortex. Possible inter- and intradomain processing differences, as estimated by ratios of these peptides, did not vary within cortex, but the intradomain peptide ratio, dyn A (l-17)/dyn A (l-81, was significantly greater in cortex than in striatum. These results indicate that prodynorphin is, in some ways, uniquely processed in the primate. Particularly unusual is the relatively low abundance of prodynorphin-derived products in the cortex, in the face of moderately high levels of kappa opiate receptor expression. Introduction morphin, and neoendorphin domains.’ Dynorphin A, which is dynorphin A (l-1 7) (dyn A (l-l 7)), can Prodynorphin, proenkephalin, and pro- be further processed into dynorphin A (l-8) (dyn A opiomelanocortin are the 3 propeptides that serve (l-8)) (Fig. 1).14.17Dyn A (l-1 7) has greater affinity as precursors to endogenous opioid peptides.
    [Show full text]
  • (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.
    [Show full text]
  • Dynorphin Opioids Present in Dentate Granule Cells May Function As Retrograde Inhibitory Neurotransmitters
    The Journal of Neuroscience, June 1994, 14(6): 37363750 Dynorphin Opioids Present in Dentate Granule Cells May Function as Retrograde Inhibitory Neurotransmitters Carrie T. Drake,’ Gregory W. Terman, lz2 Michele L. Simmons,’ Teresa A. Milner,5 Dennis D. KunkeL3 Philip A. Schwartzkroin,3B4 and Charles Chavkinl Departments of ‘Pharmacology, 2Anesthesiology, 3Neurological Surgery, and 4Physiology & Biophysics, University of Washington, Seattle, Washington 98195 and 5Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021 The granule cell population response to perforant path stim- Understanding how neuropeptides function as neurotransmit- ulation decreased significantly within seconds following re- ters has been an elusive goal. We have focused on the physio- lease of endogenous dynorphin from dentate granule cells. logical properties of the hippocampal opioid peptides, which The depression was blocked by the opioid receptor antag- are thought to be important modulators of excitability and may onists naloxone and norbinaltorphimine, suggesting that the play a role in processesassociated with both learning and mem- effect was mediated by dynorphin activation of K, type opioid ory (McDaniel et al., 1990) and epileptogenesis(Tortella et al., receptors. Pharmacological application of dynorphin B in the 1986; Hong et al., 1993). The dynorphin opioids are a family molecular layer was effective at reducing excitatory synaptic of more than five structurally related peptides that are synthe- transmission from the perforant path, but application in the sized from a common precursor (Kakidani et al., 1982) and hilus had no significant effect. These results suggest that coordinately releasedin hippocampus (Chavkin et al., 1985). endogenous dynorphin peptides may be released from a All are potent agonistsat the K, type opioid receptor (Chavkin local source within the dentate molecular layer.
    [Show full text]
  • Prodynorphin Peptide Distribution in the Forebrain of the Syrian Hamster
    THE JOURNAL OF COMPARATIlT NEUROLOGY 288353-386 (1989) Prodynorphin Peptide Distribution in the Forebrain of the Syrian Hamster and Rat: A Comparative Study With Antisera Against Dynorphin A, Dynorphin B, and the C-Terminus of the Prodynorphin Precursor Molecule CHARLES RICHARD NEAL, JB, AND SARAH WINANS NEWMAN Department of Anatomy and Cell Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0616 ABSTRACT The neuroanatomical distribution of the prodynorphin precursor mole- cule in the forebrain of the male Syrian hamster (Mesocricetus auratus) has been studied with a novel antiserum directed against the C-terminus of the leumorphin [dynorphin B (1-29)] peptide product. C-peptide staining in sec- tions from colchicine-treated hamsters is compared to staining in sections from untreated animals. In addition, the pattern of C-peptide immunostain- ing in hamster brain is compared to that in the rat brain. Finally, the C-pep- tide immunolabeling patterns in hamsters and rats are compared to those obtained with antisera to dynorphin A (1-17) and dynorphin B (1-13). Areas of heaviest prodynorphin immunoreactivity in the hamster include the hippocampal formation, lateral septum, bed nucleus of the stria termi- nalis, medial preoptic area, medial and central amygdaloid nuclei, ventral pal- lidum, substantia nigra, and numerous hypothalamic nuclei. Although this C- peptide staining pattern is similar to dynorphin staining reported previously in the rat, several species differences are apparent. Whereas moderate dentate gyrus granule cell staining and no CA4 cell staining have been reported in the rat hippocampal formation, intense immunostaining in the dentate gyrus and CA4 cell labeling are observed in the hamster.
    [Show full text]