WO1980000216A1 - Inhibition par des peptides de la tolerance et de la dependance physiques a la morphine - Google Patents

Inhibition par des peptides de la tolerance et de la dependance physiques a la morphine Download PDF

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Publication number
WO1980000216A1
WO1980000216A1 PCT/US1979/000492 US7900492W WO8000216A1 WO 1980000216 A1 WO1980000216 A1 WO 1980000216A1 US 7900492 W US7900492 W US 7900492W WO 8000216 A1 WO8000216 A1 WO 8000216A1
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WO
WIPO (PCT)
Prior art keywords
pro
leu
morphine
gly
tolerance
Prior art date
Application number
PCT/US1979/000492
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English (en)
Inventor
R Walter
Original Assignee
Univ Illinois
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Univ Illinois filed Critical Univ Illinois
Publication of WO1980000216A1 publication Critical patent/WO1980000216A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • This invention relates to novel compositions and to methods for inhibiting the development of tolerance to and dependence on drugs of the opioid type without substantial alteration of their analgesic effects. More particularly, the invention relates to compositions comprising opioid drugs and certain peptides and to administration of these compositions to obtain the desired inhibiting effect. In a specific aspect, the invention relates to pretreatment with certain peptides followed by daily administration of the peptide during chronic morphine treatment.
  • non-disulfide-containing linear hormone fragments such as MSH-release inhibiting factor, prolyl-leucyl-glycyla ide, N-carbobenzoxy-prolyl- leucyl-glycylamide, enzymatically stable cyclo(leucyl- glycine) , and prolyl-arginyl-glycylamide also exhibit these effects (Walter, R. , et al., Proc. Natl. Acad. Sci. USA, 72, 4180-4184[1975]).
  • Z-Pro-A where Z represents a protecting group such as an N-carbobe zoxy group, and A represents an a ino acid moiety selected from the group consisting of Leu, I)-Leu, Met, ⁇ Phe, Gin, S and Tyr.
  • Cyclic dipeptides having the lacta structure are als effective in the practice of this invention, particularly cyclo(Leu-Gly) and cyclo(Pro-Phe) .
  • opioid drug as used herein includes the alka ⁇ loid drugs derived from opium such as morphine, heroin, an codeine.
  • the above-identified peptides can be used effect ⁇ ively with these drugs, and more generally with opioid dru as defined by W. K. Martin, Pharmacological Developments, 19_, 463-552(1967) which citation is incorporated herein by reference.
  • the opioid drug and peptide can be administered by methods well known in the art. For example, pretreatment with the peptide is advantageously followed by daily administration of the peptide during drug treatment.
  • the peptide and drug can also be administered sequentially, i.e. alternate administration of the peptide and drug. Further, the peptide and drug can be administered simultaneously. In the last-mentioned method of
  • composition comprising the opioid drug and the peptide
  • the peptide comprises an amount sufficient to inhibit development of tolerance to and dependence on the drug.
  • Figure. 1 illustrates the inhibition of development of physical dependence (abrupt withdrawal) by Z-Pro-D_-Leu.
  • Swiss Webster mice were implanted with either morphine or placebo tablets for a period of 3 days. Following removal of the pellets, body temperature and body weight were followed for 10 hours.
  • Panel "(a.) represents the change in body temperature: ( ⁇ -- ⁇ ) Z-Pro-p_-Leu/morphine; (0--0) vehicle/morphine; (A--A) Z-Pro-D_-Leu/placebo ; (•--•) vehicle/placebo.
  • Panel (b) represents the maximal loss in body weight' ' during the same period.
  • Figure 2 illustrates the inhibition of the development of physical dependence (naloxone-precipitated withdrawal) by Z-Pro-D-Leu. Particularly illustrated is the effect of increasing doses of naloxone on body temperature 30 min. post injection in various groups of two strains of mice one hour after the pellet removal.
  • the asterisk refers to the appropriate control groups (vehicle/morphine, vehicle/placebo, and peptide/placebo) for single injection of Z-Pro-3D-Leu given only on the third day of morphine treatment were tested; since these control groups did not differ from similar groups receiving multiple injections of peptide or vehicle, they are not shown.
  • mice Male C57B1/6J, Swiss Webster, and ICR mice weighing 26 +_ 4 g (SD) were used in these studies.
  • mice were randomly divided into two . groups .
  • OMPI received the peptide under investigation (50 ⁇ g/mouse on da one) . Two hours later the mice were further subdivided and each subgroup was implanted with placebo or morphine pellet The injections of vehicle and peptide were repeated 24 and 48 hours after the first injection in their respective grou Morphine pellets containing 75 mg of morphine free base were implanted subcutaneously (SC) between 10-11 A.M. and were removed 3 days later at the same time. The control animals were implanted with placebo pellets . Body temperature and weight were measured daily at 11 A.M.
  • the peptide or vehicle was injected only once o the third day of the morphine or placebo pellet implanta ⁇ tion (25 hours prior to the removal of the pellet) .
  • the abstinence syndrome was precipitated using the morphine antagonist naloxone (Endo Laboratories Inc., N. Y.) at the appropriate dose
  • Placebo implanted mice were treated in the same manner as the morphine pellet implanted mice.
  • ICV intracerebroventricularly
  • mice Brain levels of morphine were measured in mice which received either the peptide or vehicle injections. For these studies mice were also sacrificed on the third day following morphine implantation. The mice were then sacrificed by decapitation, brains were rapidly removed, frozen on dry ice, and stored at -80°C until assay for morphine content. Brain morphine concentrations were determined fluorometric- ally CBhargava, H. N. , J. Pharma. Sci., j36_, 1044-1045[1977]) . Statistical analysis unless otherwise noted for the above experiments was performed according to Winer (Winer, B, J. , Statistical Principles in Experimental Design (McGraw-Hill,- New York, N. Y.), p. 208, 1962) by the Student's t-test, and all data are expressed as means +_ standard deviations.
  • mice Male ICR, C57B1/6J, and Swiss Webster mice were used. The two-compartment passive avoidance box and details of the procedure have been described by Rainbow, T, C, et al., Pharmaca. Biochem. Behav. , 4_, 347-349(1976).
  • ICR mice Five seconds after entering the large compartment, ICR mice received 0,4 mA of scrambled foot shock for 0.8 seconds; Swiss mice, 0.3 mA for 0.8 seconds; and C57B1/6J mice, 0,2 mA for 2 seconds.
  • Several agents have been found to be amnesic under these conditions.
  • mice were injected SC with 100 ⁇ g of peptide in saline or • with saline alone. Mice were tested for retention 24 hours later. Mice that failed to enter the large compartment on testing within 180 seconds were removed and given a score
  • mice which received the Z-Pro-D-Leu injection only on the third day responded as did the vehicle/morphine-treated mice, i.e. the injection of naloxone produced a hypothermic response in these animals which was not significantly different from that produced in the vehicle/morphine group ( Figure 2) .
  • Morphine treated Swiss Webster mice given vehicle were tolerant to the hyperthermic (P ⁇ 0.001) and analgesic (P ⁇ 0.001) effects of the ICV injection of 40 ⁇ g of morphine when- compared to the vehicle placebo group (see Table I) . This tolerance was evident for 24 hours after removal of the pellets.
  • a similar diminished response after the ICV injection of 40 ⁇ g of morphine was found in C57B1/6J mice both for hypothermia (P ⁇ 0.01) and for analgesia (P ⁇ 0.001).
  • Mice, which had been given Z-Pro-D-Leu during chronic mor ⁇ phine treatment responded to the ICV injection of morphine in a manne which was not significantly different from morphine-naive mice, but was significantly different from Table I
  • mice O vehicle/morphine-treated mice (P ⁇ 0.01).
  • the mice responded similarly to those which had received the vehicle injection and morphine, i.e. giving the peptide after the development of tolerance to morphine did not effectively alter the manifestation of tolerance. It is also significant that there was no difference in the response to the challenge dose of morphine between the placebo-implanted mice which;received the peptide in either strain and the placebo-implanted mice which received the vehicle injections (P ⁇ 0.01).
  • N- ⁇ carbobenzoxy (Z) did not alter the activity of the peptide in these tests, but addition of Z-Gly or substitution of
  • Another group of peptides that yielded active deriva ⁇ tives are the cyclic dipeptides possessing the lactam struc ⁇ ture. Among those tested, cyclo(Leu-Gly) and cyclo(Pro-Phe) showed significant activity.
  • the peptides of this invention inhibit development of physical dependence, which accompanies chronic administration of morphine, since body weight and temperature of animals given -both substances on a chronic basis did not alter during abstinence precipitated by naloxone or by withdrawal of the morphine.
  • the peptides of this invention can be administered during morphine treatment in amounts ranging from about 0.002 to about 100 mg/kg of body weight.
  • the dosage will vary with the method of administration, with the particular species of animal treated, and with the activity of the peptide employed.
  • a dipeptide such as Z-Pro-j-Leu
  • a dosage in the range of about 0.20 to about 20 mg/kg can be employed advantageously;
  • a tripeptide such as Pro-Leu-Gly-NH 2 , a dosage in the range of about 0.02 to about 20 mg/kg; and with a cyclic peptide such as cycloCLeu-Gly) , a dosage in the range of about 0.002 to about 20 mg/kg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Certains peptides administres pendant un traitement chronique a la morphine se sont reveles etre efficaces dans la prevention du developpement de la tolerance et de la dependance physiques. Les peptides particulierement efficaces sont le prolyle-leucyle-glycinamide, le cyclo (leucyleglycle), et le peptide protege- N-carbobenzoxy-prolyle-D-leucyle, qui, injectes quotidiennement dans des souris recevant un traitement chronique de morphine, ont empeche le developpement de la dependance physique, ce qui a ete mesuree par des changements de la temperature et du poids du corps, soit lors d'un arret brusque ou sous naloxone. Toutefois l'injection d'un peptide le dernier jour seulement du traitement a morphine n'a pas altere les signes manifestes de l'arret. L'injection quotidienne d'un peptide s'est revelee egalement efficace pour bloquer le developpement de la tolerance aux effets analgesiques et hypothermiques de doses ulterieures provocatrices de morphine. Le traitement de peptides n'a pas altere les effets aigus de la morphine sur l'analgesie ou la temperature du corps. Aucun effet sur la memoire n'a ete remarque comme cela a pu etre evalue dans un exercice d'epreuve a annulation passive.
PCT/US1979/000492 1978-07-10 1979-07-09 Inhibition par des peptides de la tolerance et de la dependance physiques a la morphine WO1980000216A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US92318778A 1978-07-10 1978-07-10
US923187 1978-07-10
US4670179A 1979-06-08 1979-06-08

Publications (1)

Publication Number Publication Date
WO1980000216A1 true WO1980000216A1 (fr) 1980-02-21

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099057A2 (fr) * 1982-07-14 1984-01-25 BASF Aktiengesellschaft Dérivés N-acylés de peptides, leur préparation et utilisation dans la lutte contre les maladies et moyen de lutte
EP0087750A3 (en) * 1982-02-25 1984-02-01 Pfrimmer + Co., Pharmazeutische Werke Erlangen Gmbh Amino acid preparations containing glutaminic residues
EP0362555A1 (fr) * 1988-09-03 1990-04-11 Hoechst Aktiengesellschaft Pipérazinediones à activité psychotrope
US20220106365A1 (en) * 2017-06-02 2022-04-07 Second Genome, Inc. Proteins for the treatment of epithelial barrier function disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112521457B (zh) * 2020-12-29 2022-03-01 潍坊医学院 一种分离自华蟾素注射液的镇痛肽ci118及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093713A (en) * 1977-02-28 1978-06-06 Ayerst Mckenna & Harrison Ltd. Dipeptide derivatives with central nervous system activity and preparation thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093713A (en) * 1977-02-28 1978-06-06 Ayerst Mckenna & Harrison Ltd. Dipeptide derivatives with central nervous system activity and preparation thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Proc. Nat'l Acad. Sci. published January 1979, pages 1-3 WALTER, et al. *
The Merck Index, 1976, No. 6115, pages 815, MARTHA WINDHOLZ, et al. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0087750A3 (en) * 1982-02-25 1984-02-01 Pfrimmer + Co., Pharmazeutische Werke Erlangen Gmbh Amino acid preparations containing glutaminic residues
EP0099057A2 (fr) * 1982-07-14 1984-01-25 BASF Aktiengesellschaft Dérivés N-acylés de peptides, leur préparation et utilisation dans la lutte contre les maladies et moyen de lutte
EP0099057A3 (en) * 1982-07-14 1984-09-12 Basf Aktiengesellschaft N-acyl derivatives of peptides, their manufacture and use in combating diseases and means therefor
EP0362555A1 (fr) * 1988-09-03 1990-04-11 Hoechst Aktiengesellschaft Pipérazinediones à activité psychotrope
US20220106365A1 (en) * 2017-06-02 2022-04-07 Second Genome, Inc. Proteins for the treatment of epithelial barrier function disorders

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Publication number Publication date
EP0016136A1 (fr) 1980-10-01

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