EP0777682A1 - Nouveaux antagonistes des peptides opioides - Google Patents

Nouveaux antagonistes des peptides opioides

Info

Publication number
EP0777682A1
EP0777682A1 EP95923629A EP95923629A EP0777682A1 EP 0777682 A1 EP0777682 A1 EP 0777682A1 EP 95923629 A EP95923629 A EP 95923629A EP 95923629 A EP95923629 A EP 95923629A EP 0777682 A1 EP0777682 A1 EP 0777682A1
Authority
EP
European Patent Office
Prior art keywords
tic
phe
tyr
cha
formula
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95923629A
Other languages
German (de)
English (en)
Inventor
Peter-Appartement 1212 SCHILLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
Astra AB
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 Astra AB filed Critical Astra AB
Priority claimed from PCT/SE1995/000721 external-priority patent/WO1995035316A1/fr
Publication of EP0777682A1 publication Critical patent/EP0777682A1/fr
Withdrawn legal-status Critical Current

Links

Definitions

  • This invention is related to a new class of opioid peptide analogs that are ⁇ opioid receptor antagonists as well as to their synthesis and their use as analgesic and immunosuppressive compounds.
  • a known nonpeptide ⁇ opioid antagonist is naltrindole, which is described by P.S
  • Naltrindole has similar ⁇ antagonist, potency as the compounds according to this invention but is much less ⁇ selective.
  • ICI 174864 is much less ⁇ -selective (10-300 times less) and has much lower antagonist potency in the MVD assay (40-1000 times less potent).
  • the problem underlying the present invention was to find ⁇ opioid antagonists both with high ⁇ antagonist potency and with high ⁇ selectivity.
  • R3, R4, R5 and R are all H;
  • R_ is H or a Ci-C ⁇ alkyl group; R9 is selected from
  • R j0 is OH, NH 2 or
  • R l i is H, NO 2 , F, Cl, Br or I; q is 0-3;
  • R l is COOH, CONH 2 , CH 2 OH, or any additional amino acid or peptide segment; or
  • R l is as defined above.
  • Preferred compounds of the invention are those compounds wherein Rl is selected from H or CH3;
  • R is selected from H or CH3; R3 is selected from H or CH3; R 4 is H; R 5 is H;
  • Rg is selected from H or CH3;
  • R7 is selected from CO or CH 2 ;
  • Rg is selected from H or CH3;
  • R9 is selected from .
  • RlO is selected from R! , wterein Ri ! is H, NO 2 , F, Cl, Br or I,
  • EspeciaUy preferred compounds of the invention are those compounds wherein Rl is selected from H or CH3;
  • R 2 is selected from H or CH3;
  • R3 is selected from CH3;
  • R4 is selected from H
  • R5 is selected from H
  • R6 is selected from CH3;
  • R7 is selected from CH 2 ;
  • R_ is selected from H or CH3;
  • R 10 is selected from R ⁇ , wherein R ⁇ is H, q is L and R i2 is COOH.
  • R9 is — CH 2 — CH
  • R4 and R5 are hydrogen and R3 and R ⁇ are both methyl groups.
  • R7 is a part of a reduced peptide bond.
  • peptides were hydrolyzed in 6N HC1 containing a small amount of phenol for 24 h at 110°C in deaerated tubes (in some case hydrolyses lasting for 12 and 48 h were also performed to take into account amino acid degradation). Hydrolysates were analyzed on a Beckman Model 121 C amino acid analyzer equipped with a system AA computing integrator. FAB mass spectrometry was used to estabUsh the correct molecular weights of the peptides.
  • Boc-Phe-O-resin (lg, 0.61 mmol Boc-Phe/g resin; Peninsula, Belmont, CA) was washed ⁇ with reagents in the following sequence: CH 2 C1 2 (3x 1 min), 50% (v/v) TFA in CH 2 C1 2 (30
  • Boc- Cha-OH (412 mg, 1.52 mmol) was then coupled using HOBt (205 mg, 1.52 mmol) and DCC (313 mg, 1.52 mmol) in C ⁇ Cl ⁇ MF (3:1, v v) for 17h. The resin was then washed
  • the resin was washed with CH 2 Q (3x1 min) and EtOH (3x1 min) and was dried in a desiccator.
  • the dry resin was treated with 20 ml of HF plus 1 ml of anisole (per gram of resin) first for 90 min at 0 ° C and then for 15 min at room temperature. After evaporation of the HF, the resin was extracted three times with Et 2 O and, subsequently three times with
  • the peptide was purified by gel filtration on a Sephadex-G-25 column in 0.5 N AcOH foUowed by reversed-phase chromatography on an octadecasilyl siUca column with a linear gradient of 0-80% MeOH in 1% TFA. After solvent evaporation the pure peptide was dissolved in cone. AcOH and was obtained in soUd form through lyophilization.
  • Biosassys based on inhibition of electricaUy evoked contractions of the mouse vas deferens (MVD) and of the guinea pig ileum (GPI) were made.
  • the opioid effect is primarily mediated by ⁇ opioid receptors
  • the inhibition of the . contractions is mostly due to interaction with ⁇ opioid receptors.
  • Antagonist potencies in these assays are expressed as so-called K ⁇ -values (H.W. KosterUtz & AJ. Watt, Br. J.
  • Peptides containing a cyclohexylalanine (Cha) residue in the 3-position of the peptide sequence are more potent ⁇ antagonists than corresponding peptides with an aromatic amino acid in position 3.
  • All compounds showed no ⁇ antagonist activity in the GPI assay at concentrations as high as 10 ⁇ M.
  • Kj ⁇ , Kj ⁇ opioid receptor binding constants of the compounds were determined by displacement of relatively selective ⁇ and ⁇ radioligands from binding sites in rat brain membrane preparations (calculated from the measured IC50 values on the basis of the equation by Cheng & Prusoff (Y.C. Cheng and W.H. Prusoff (Biochem. Pharmacol. 22, 3099-3102 (1973)). Opioid receptor binding studies
  • the ⁇ -, ⁇ - and -opioid receptor affinities of aU new analogs were determined in binding assays based on displacement of ⁇ -, ⁇ -and K-selective radioUgands from rat brain membrane binding sites.
  • K-ligands guinea pig brain homogenates were used, since the relative proportion of K-binding sites is higher in guinea pig brain than in rat brain.
  • the experimental procedure being used in our laboratory represents a modified version of the binding assay described by Pasternak et al. (Mol. Pharmacol. 11, 340-351, (1975)).
  • AUquots (2 ml) of the membrane preparations were incubated for 1-2 h at 25°C with 1 ml standard buffer containing the peptide to be tested and one of the foUowing radioUgands at the final concentration indicated: [ 3 H]DAMGO, ⁇ -selective, 0.7 nM; [ 3 H]DSLET, [1HJDPDPE, or [ 3 H]TIPP, ⁇ - selective, 1.0 nM; and [ 3 H]U69,563, K-selective, 0.5 nM. The incubation was terminated by filtration through Whatman GF/B filters under vacuum at 4°C.
  • Kj binding inhibition constants
  • Ratios of the Kj-values in the ⁇ -, ⁇ - and K-representative binding assays are a measure of the receptor selectivety of the compound under investigation (e.g. Kj ⁇ /Kj ⁇ indicates the selectivity for ⁇ - receptors versus ⁇ -receptors). None of the compounds according to the claimed invention had significant affinity for K-receptors.
  • the ⁇ antagonists may be used in combination with analgesics of the ⁇ agonist type (e.g. morphine) to prevent the development of tolerance and dependence, as suggested by the results of E.E. Abdelhamid et al., J. Parmacol. Exp. Ther. 258. 299-303 (1991).
  • analgesics of the ⁇ agonist type e.g. morphine
  • the ⁇ antagonists according to the invention may also be therapeutically useful as immunosuppressive agents.
  • Immunosuppressive effects of the less ⁇ -selective and less "pure" ⁇ antagonist naltrindole have been described by K. Arakawa et al. Transplantation Proc. 24, 696-697 (1992); Transplantation 53, 951-953 (1992).
  • DAMGO H-Tyr-D-Ala-Gly-Phe(N ⁇ Me)-Gly-ol
  • DCC dicyclohexylcarbodiimide
  • DIEA d ⁇ sopropylethylamine
  • Dmt 2',6'-dimethyltyrosine
  • DPDPE [D-Pen 2 ,D-Pen 5 ]enkephalin
  • DSLET H-Tyr-D-Ser-Gly-Phe-Leu-Thr-OH
  • FAB-MS fast atom bombardment mass spectrometry
  • GPI guinea pig Ueum
  • HOBt 1-hydroxybenzotriazole
  • MVD mouse vas deferens
  • TIPP H-Tyr-Tic-Phe-Phe-OH
  • U69,593 (5 ⁇ , la, 8 ⁇ )-(-)-N-methyl-[7-(l-py ⁇ olidinyl)-l-oxaspiro[4,5]dec-8- yl] benzeneacetamide

Landscapes

  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur des composés de formule (I), leur procédé d'obtention, leurs préparations pharmaceutiques et leurs utilisations, ces composés ayant des applications thérapeutiques, notamment comme analgésiques et comme antidépresseurs.
EP95923629A 1994-08-25 1995-06-14 Nouveaux antagonistes des peptides opioides Withdrawn EP0777682A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9402838A SE9402838D0 (sv) 1994-08-25 1994-08-25 New compounds
SE9402838 1994-08-25
PCT/SE1995/000721 WO1995035316A1 (fr) 1994-06-20 1995-06-14 Nouveaux antagonistes des peptides opioides

Publications (1)

Publication Number Publication Date
EP0777682A1 true EP0777682A1 (fr) 1997-06-11

Family

ID=20395024

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95923629A Withdrawn EP0777682A1 (fr) 1994-08-25 1995-06-14 Nouveaux antagonistes des peptides opioides

Country Status (2)

Country Link
EP (1) EP0777682A1 (fr)
SE (1) SE9402838D0 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9535316A1 *

Also Published As

Publication number Publication date
SE9402838D0 (sv) 1994-08-25

Similar Documents

Publication Publication Date Title
AU681372B2 (en) New peptides
US5789531A (en) Peptide-based inhibitors of HIV replication
US5455230A (en) Delta opioid receptor antagonists and their use as analgesic agents
JPH09511500A (ja) Ｎ−置換化グリシンを含むブラジキニン拮抗薬ペプチド
Schiller et al. Conformationally restricted deltorphin analogs
US5811400A (en) Peptide derivatives with δ opioid receptor antagonist or mixed μ agδ antagonist effects
JPS61191698A (ja) 新規な環状ヘキサペプチドｌｈｒｈ拮抗剤
US5733881A (en) Opioid peptide antagonists
US4103005A (en) Novel-enkephalin analogs
CA1339679C (fr) Analogues de lhrh de taille reduite
AU691630C (en) New opioid peptide antagonists
EP0777682A1 (fr) Nouveaux antagonistes des peptides opioides
US5786447A (en) Opioid peptide analogs
Rovero et al. Synthesis and biological activity of N-methylated analogues of Neukokinin A
CA2088664A1 (fr) Pentapeptides immunoregulatoires et neuroregulatoires
SUZUKI et al. Studies on Analgesic Oligopeptides. V. Structure-Activity Relationship of Tripeptide Alkylamides, Tyr-D-Arg-Phe-X
US4422968A (en) β-Endorphin analogs

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19970325

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

RAX Requested extension states of the european patent have changed

Free format text: LT PAYMENT 970325;LV PAYMENT 970325;SI PAYMENT 970325

17Q First examination report despatched

Effective date: 19991115

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ASTRAZENECA AB

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20000326