EP0777682A1 - Neue antagonisten für opioidpeptide - Google Patents
Neue antagonisten für opioidpeptideInfo
- 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- Withdrawn
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
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9402838 | 1994-08-25 | ||
SE9402838A SE9402838D0 (sv) | 1994-08-25 | 1994-08-25 | New compounds |
PCT/SE1995/000721 WO1995035316A1 (en) | 1994-06-20 | 1995-06-14 | New opioid peptide antagonists |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0777682A1 true EP0777682A1 (de) | 1997-06-11 |
Family
ID=20395024
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95923629A Withdrawn EP0777682A1 (de) | 1994-08-25 | 1995-06-14 | Neue antagonisten für opioidpeptide |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP0777682A1 (de) |
SE (1) | SE9402838D0 (de) |
-
1994
- 1994-08-25 SE SE9402838A patent/SE9402838D0/xx unknown
-
1995
- 1995-06-14 EP EP95923629A patent/EP0777682A1/de not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO9535316A1 * |
Also Published As
Publication number | Publication date |
---|---|
SE9402838D0 (sv) | 1994-08-25 |
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Legal Events
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17Q | First examination report despatched |
Effective date: 19991115 |
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