Peptides are agonists of k-opioid receptor

 

The invention relates to a synthetic amide of opioid peptide or its pharmaceutically acceptable salt having affinity against-opioid receptor, which is at least 1000 times greater than its affinity in relation to-opioid receptor, and which reveals long-term effect when introduced in vivo, and this peptide has the following formula: H-Xaa1-Xaa2-Xaa3-Xaa4-Q, where Xaa1shown are (A)D-Phe,D-Tyr, D-Tic, or D-Ala (cyclopentyl or thienyl), and A - N, NO2, F, Cl or CH3; Xaa2(A')D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, where A' - or 3,4 Cl2; XAA3- D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala (cyclopentyl), and In - N or CMe; XAA4represents the D-Arg, D-Har, D-nArg, D-Lys, D-i.l.y bit, D-Arg (Et2), D-Har(Et2), D-Amf, D-Gmf, D-Dbu, D-Orn or D-Ior; a Q - NR1R2morpholinyl, thiomorpholine, (C)piperidinyl, piperazinil, 4-one or 4,4-disubstituted piperazinil or-lysyl, where R1is lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, aminocyclohexanol, 2-thiazolyl, 2-pikolinos, 3-pikolinos, 4-picolyl is or lower alkyl; With - N, 4-hydroxy or 4-oxo. The technical result is an increase in the affinity against-opioid receptors, long-term obezbolivaushee activity in vivo. 3 C. and 20 C. p. F.-ly, 9 PL.

Tablicy

Claims

1. Synthetic amide of opioid peptide or its pharmaceutically acceptable salt having affinity against-opioid receptor, which is at least 1000 times greater than its affinity in relation to-opioid receptor, and which reveals long-term effect when introduced in vivo, and this peptide has the following formula:

H-Xaa1-Xaa2-Xaa3-Xaa4-Q,

where XAA1shown are (A)D-Phe, (CMe)D-Phe, D-Tyr, D-Tic, or D-Ala (cyclopentyl or thienyl), and A - N, NO2, F, Cl or CH3;

XAA2represents (A')D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, where A' - or 3,4 Cl2;

XAA3represents the D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala (cyclopentyl), and In - N orIU;

Xaa4represents the D-Arg, D-Har, D-nArg, D-Lys, D-i.l.y bit, D-Arg (Et2), D-Har(Et2), D-Amf, D-Gmf, D-Dbu, D-Orn or D-Ior;

Q - NR-lysyl, where R1is lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, aminocyclohexanol, 2-thiazolyl, 2-pikolinos, 3-pikolinos, 4-pikolinos,(acylamino)-polymethene or 4-polyoxyethylene group, a R2is H or lower alkyl; C - H, 4-hydroxy or 4-oxo.

2. Synthetic peptide under item 1, and XAA2represents D-Phe, XAA3- D-Leu or D-Nle, and XAA4- D-Arg or D-Orn.

3. Synthetic peptide under item 1 or 2, and Q other1, a R1is ethyl, propylene, bootrom, cyclopropyl or cyclobutyl.

4. Synthetic peptide under item 1 or 2, and Q is morpholinyl or thiomorpholine.

5. Synthetic peptide under item 1 or 2, and Q represents other1where R1- 4-picolyl.

6. Synthetic peptide under item 1 or 2, and Q represents N(Et)2, NH(Aeb), Ppz or Pcp.

7. Synthetic peptide under item 1 or 2, and Q represents other1where R1- AAO, AEO, Hoh, Ghx or Gao.

8. Synthetic peptide according to any one of paragraphs.1-7, and Xaa1- D-Phe, D-l(2-thienyl) or D-4Fpa.

9. Synthetic peptide under item 1, and XAA4- D-Gmf.

10. Synthetic peptide under item 1, and XAA2- D-4Cpa or D-3,4 CPA.

H-Xaa1-Xaa2-Xaa3-Xaa4-Q,

where Xaa1represents D-Phe (unsubstituted or substituted WithIU, 2F, 4F or 4l) or D-Ala (cyclopentyl or thienyl);

Xaa2(A')D-Phe, D-lNal, D-2Nal or D-Trp, where a' - N, 4F, 4l, 4NO2or 3,4 CL2;

XAA3- D-NIe, D-Leu, D-CML, D-Met or D-Acp;

XAA4- D-Arg, D-Arg(Et2), D-Lys, D-i.l.y bit, D-Har, D-Har(Et2), D-nArg, D-Orn, D-Ior, D-Dbu, D-Amf and D-Gmf;

Q - NR1R2Could Tmo, Pip, 4-HyP, Ochre or Ppz, where R1represents Me, Et, Pr, Bu, hEt, sur, Bzl or 4-picolyl, a R2- N or Et.

12. Synthetic peptide on p. 11, and XAA2- D-Phe, D-SRA or D-3,4 Cpa; XAA3- D-Leu or D-Nle; XAA4- D-Arg, D-Orn or D-Gmf.

13. Synthetic peptide under item 11 or 12, and Q represents other1where R1is Et, hEt, Pr or 4-pikolinos.

14. Synthetic peptide under item 11 or 12, and Q is - N(Et2) or NN(b).

15. Synthetic peptide under item 11 or 12, and Q - morpholinyl or thiomorpholine.

16. Synthetic peptide under item 11 or 12, and Q is other1where R1is ethyl or 4-pikolinos.

17. Synthetic peptide under item 11 or 12, and Q - Ppz, PCP or NH(Hoh).

18. Synthetic peptide according to any one of paragraphs.11-17, and Xaa1- D-Phe or D-l(2-thienyl) or D-Fpa.

19. Synthetically the silt,

H-D-Phe-D-Phe-D-Nle-D-Arg-NH-4-picolyl,

H-D-Phe-D-Phe-D-Nle-D-Arg-NHPr,

N-D-h-D-h-D-Nl-D-Agde-thiomorpholine,

H-D-Phe-D-Phe-D-Nle-D-Arg-Net2,

H-D-Phe-D-Phe-D-Nle-D-Arg-NHMe,

N-D-h-D-h-D-Lu-D-UCP-morpholinyl,

H-D-4Fpa-D-Phe-D-Nle-D-Arg-NH-4-picolyl,

H-D-Phe-D-Phe-D-Nle-D-Arg-NH-cyclopropyl,

H-D-Ala(2Thi)-D-3,4 Cpa-D-Leu-D-Arg-morpholinyl,

H-D-Phe-D-Phe-D-Nle-D-Gmf-morpholinyl,

H-D-Phe-D-Phe-D-Leu-D-Orn-NH(Aeb),

N-D-h-D-h-D-Lu-D-Ls-morpholinyl,

H-D-Phe-D-Phe-D-Nle-D-Arg-piperazinil, and

H-D-Phe-D-Phe-D-Nle-D-Arg-NH(Hoh).

20. Synthetic peptide under item 1, characterized by the value of the ED50approximately 0.5 mg/kg or less, and this peptide is characterized by the following formula:

H-Xaa1-Xaa2-Xaa3-Xaa4-Q,

where Xaa1- D-Phe, D-4Fpa, D-2Fpa, D-Acp or D-Ala(2Thi);

XAA2(A)D-Phe, D-1Nal, D-2Nal or D-Trp, where a is a 4F or 4l;

XAA3- D-Nle, D-Met or D-Leu;

Xaa4- D-Arg, D-Har, D-nArg, D-Lys, D-On or D-Gmf;

Q - other1Could Tmo, Pip or Ppz, and R1is a Et, Pr or 4 Pic.

21. Synthetic peptide under item 1, characterized by the value of the ED50approximately 0.5 mg/kg or less, and this peptide is characterized by the following formula:

H-Xaa1-Xaa2-Xaa3-Xaa4-Q,

where Xaa1represents D-Phe, D-4Fpa, D-2Fpa or D-Ala(2Thi);

Xaa2(A)D-Phe, D-lNal, D-2Nal or D-TCP, Ppz or N(Et)2and R1- Et, Pr, sur, 4Pic, Aeb or Hoh.

22. Pharmaceutical composition having agonistic activity against-opioid receptor, which contains a pain-relieving amount of a synthetic peptide described in any of paragraphs.1-21, and pharmaceutically acceptable liquid or solid carrier.

23. A method of treating visceral pain, rheumatoid arthritis, symptoms after surgery on the abdomen or acute or chronic pain, characterized in that the method comprises the introduction of analgesic amount of a pharmaceutical composition, characterized in p. 22.

 

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