Opioid agonist peptides and uses thereof

1. A method of inhibiting or reducing pain or gastrointestinal motility in a subject in need thereof, comprising providing to the subject an effective amount of an opioid agonist peptide comprising or consisting of an amino acid sequence of Formula Ia:

(SEQ ID NO: 357)

X1-X2-X3-X4-X5 (Formula Ia)

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

X1 is Tyr, DMT, or Phe(4-COX);

X2 is any amino acid;

X3 is any amino acid;

X4 is Sar, or bhF unsubstituted or substituted with 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, or 4-OH; and

X5 is absent or any amino acid;

wherein DMT is 2,6-dimethyltyrosine;

Phe(4-COX) is substituted or unsubstituted

wherein X is substituted or unsubstituted OH or NH 2 ; and

provided that when X1 is Tyr; then X4 is bhF unsubstituted or substituted with 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, or 4-OH, and X5 is N-methylamino acid.

2. The method of claim 1 , wherein the peptide is according to Formula XIIIa, XIIIb, or XIIIc:

(SEQ ID NO: 343)

R 1 -DMT-X2-X3-bhF-X5-R 2  (XIIIa);

(SEQ ID NO: 344)

R 1 -Phe(4-COX)-X2-X3-bhF-X5-R 2  (XIIIb);

or

(SEQ ID NO: 345)

R 1 -Tyr-X2-X3-bhF-X5-R 2  (XIIIc);

wherein DMT, Phe(4-COX), X2, X3 and X5 are as described in claim 1 ; bhF is unsubstituted or substituted with 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, or 4-OH; R 1 is H or acetyl; and R 2 is OH or NH 2 ;

provided that when the peptide is according to formula XIIIc, then X5 is a N-methylamino acid.

3. The method of claim 1 , wherein X3 is (D)Phe, Phe, Bip, His, Aba, Trp, homo-Phe, 1-Nal, Phe(4-F), Phe(4-CN), Tic, Phe(3,4-dichloro), Phe(4-tBu), Phe(3,4-dimethoxy), DPA, Gly, Sar, THP, Ala, Leu, Ile, Val, Aib, or Ala.

4. The method of claim 1 , wherein the amino acid sequence is according to Formula XIVa, XIVb, or XIVc:

(SEQ ID NO: 346)

R 1 -DMT-X2-G-bhF-X5-R 2  (XIVa);

(SEQ ID NO: 347)

R 1 -Phe(DMC)-X2-G-bhF-X5-R 2  (XIVb);

or

(SEQ ID NO: 348)

R 1 -Tyr-X2-G-bhF-X5-R 2  (XIVc)

wherein Phe(DMC) is Phe(2,6-dimethyl-4-CONH 2 ); R 1 is H or acetyl; and R 2 is OH or NH 2 .

5. The method of claim 1 , wherein X2 is (D)Glu, (D)Arg, N(Me)-(D)Ala, (D)Ala, (D)Tic, (D)Lys, (D)Orn, (D)Thr, (D)Asp, or (D)Tyr.

6. The method of claim 1 , wherein the amino acid sequence is according to Formula XVa, XVb, XVc, XVd, XVIa, XVIb, XVIc, or XVId:

(SEQ ID NO: 349)

R 1 -DMT-(D)Ala-G-bhF-X5-R 2  (XVa);

(SEQ ID NO: 350)

R 1 -DMT-(D)Asp-G-bhF-X5-R 2  (XVb);

(SEQ ID NO: 351)

R 1 -DMT-(D)Thr-G-bhF-X5-R 2  (XVc);

(SEQ ID NO: 352)

R 1 -DMT-(D)Glu-G-bhF-X5-R 2  (XVd);

(SEQ ID NO: 353)

R 1 -Phe(DMC)-(D)Ala-G-bhF-X5-R 2  (XVIa);

(SEQ ID NO: 354)

R 1 -Phe(DMC)-(D)Asp-G-bhF-X5-R 2  (XVIb);

(SEQ ID NO: 355)

R 1 -Phe(DMC)-(D)Thr-G-bhF-X5-R 2  (XVIc);

(SEQ ID NO: 356)

R 1 -Phe(DMC)-(D)Glu-G-bhF-X5-R 2  (XVId)

wherein R 1 is H or acetyl; and R 2 is OH or NH 2 .

7. The method of claim 1 , wherein X5 is (D)Glu, (D)Arg, N(Me)-(D)Ala, (D)Ala, (D)Tic, (D)Lys, (D)Orn, (D)Thr, (D)Asp, (D)Tyr, Sar, N(Me)Phg, N(Me)Cha, N(Me)Tyr, N(Me)Nle, N(Me)Ile, N(Me)Ala, N(Me)Val, N(Me)Leu, or N(Me)Phe.

8. The method of claim 1 , wherein the amino acid sequence is according to Formula XVIIa, XVIIb, XVIIc, XVIId, XVIIe, XVIIf, XVIIg, XVIIh, XVIIi, XVIIj, XVIIk, XVIII, XVIIIa, XVIIIb, XVIIIc, XVIIId, XVIIIe, XVIIIf, XVIIIg, XVIIIh, XVIIIi, XVIIIj, XVIIIk, or XVIIIl:

(SEQ ID NO: 43)

R 1 -DMT-(D)Ala-G-bhF-Sar-R 2  (XVIIa);

(SEQ ID NO: 82)

R 1 -DMT-(D)Asp-G-bhF-Sar-R 2  (XVIIb);

(SEQ ID NO: 82)

R 1 -DMT-(D)Thr-G-bhF-Sar-R 2  (XVIIc);

(SEQ ID NO: 187)

R 1 -DMT-(D)Glu-G-bhF-Sar-R 2  (XVIId);

(SEQ ID NO: 111)

R 1 -DMT-(D)Ala-G-bhF-NMeAla-R 2  (XVIIe);

(SEQ ID NO: 170)

R 1 -DMT-(D)Asp-G-bhF-NMeAla-R 2  (XVIIf);

(SEQ ID NO: 183)

R 1 -DMT-(D)Thr-G-bhF-NMeAla-R 2  (XVIIg);

(SEQ ID NO: 185)

R 1 -DMT-(D)Glu-G-bhF-NMeAla-R 2  (XVIIh);

(SEQ ID NO: 113)

R 1 -DMT-(D)Ala-G-bhF-NMeIle-R 2  (XVIIi);

(SEQ ID NO: 172)

R 1 -DMT-(D)Asp-G-bhF-NMeIle-R 2  (XVIIj);

(SEQ ID NO: 182)

R 1 -DMT-(D)Thr-G-bhF-NMeIle-R 2  (XVIIk);

(SEQ ID NO: 186)

R 1 -DMT-(D)Glu-G-bhF-NMeIle-R 2  (XVIIl);

(SEQ ID NO: 70)

R 1 -Phe(DMC)-(D)Ala-G-bhF-Sar-R 2  (XVIIIa);

(SEQ ID NO: 77)

R 1 -Phe(DMC)-(D)Asp-G-bhF-Sar-R 2  (XVIIIb);

(SEQ ID NO: 76)

R 1 -Phe(DMC)-(D)Thr-G-bhF-Sar-R 2  (XVIIIc);

(SEQ ID NO: 330)

R 1 -Phe(DMC)-(D)Glu-G-bhF-Sar-R 2  (XVIIId);

(SEQ ID NO: 217)

R 1 -Phe(DMC)-(D)Ala-G-bhF-NMeAla-R 2  (XVIIIe);

(SEQ ID NO: 331)

R 1 -Phe(DMC)-(D)Asp-G-bhF-NMeAla-R 2  (XVIIIf);

(SEQ ID NO: 332)

R 1 -Phe(DMC)-(D)Thr-G-bhF-NMeAla-R 2  (XVIIIg);

(SEQ ID NO: 333)

R 1 -Phe(DMC)-(D)Glu-G-bhF-NMeAla-R 2  (XVIIIh);

(SEQ ID NO: 218)

R 1 -Phe(DMC)-(D)Ala-G-bhF-NMeIle-R 2  (XVIIIi);

(SEQ ID NO: 334)

R 1 -Phe(DMC)-(D)Asp-G-bhF-NMeIle-R 2  (XVIIIj);

(SEQ ID NO: 335)

R 1 -Phe(DMC)-(D)Thr-G-bhF-NMeIle-R 2  (XVIIIk);

or

(SEQ ID NO: 336)

R 1 -Phe(DMC)-(D)Glu-G-bhF-NMeIle-R 2  (XVIIIl);

wherein R 1 is H or acetyl; and R 2 is OH or NH 2 .

9. The method of claim 2 , wherein R 1 is H.

10. The method of claim 1 , wherein the peptide is:

(SEQ ID NO: 43)

H-DMT-a-G-bhF-Sar-NH 2 ;

(SEQ ID NO: 43)

H-DMT-a-G-bhF-Sar-OH;

(SEQ ID NO: 82)

H-DMT-((D)Thr)-Gly-(β-homoPhe)-Sar-NH 2 ;

(SEQ ID NO: 82)

H-DMT-((D)Thr)-Gly-(β-homoPhe)-Sar-OH;

(SEQ ID NO: 99)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-N(Me)Phg-OH;

(SEQ ID NO: 99)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-N(Me)Phg-NH 2 ;

(SEQ ID NO: 101)

H-Phe(2,6-dimethyl-4-CONH 2 )-(D)Ala-Gly-

(b-homoPhe)-N(Me)Nle-NH 2 ;

(SEQ ID NO: 101)

H-Phe(2,6-dimethyl-4-CONH 2 )-(D)Ala-Gly-

(b-homoPhe)-N(Me)Nle-OH;

(SEQ ID NO: 175)

H-DMT-(D)Asp-Gly-(b-homoPhe)-N(Me)Cha-OH;

(SEQ ID NO: 175)

H-DMT-(D)Asp-Gly-(b-homoPhe)-N(Me)Cha-NH 2 ;

(SEQ ID NO: 111)

H-DMT-a-G-bhF-N(Me)Ala-OH;

(SEQ ID NO: 183)

H-DMT-(D)Thr-G-bhF-N(Me)Ala-OH;

(SEQ ID NO: 83)

H-DMT-(D)Asp-G-bhF-Sar-OH;

(SEQ ID NO: 83)

H-DMT-(D)Asp-G-bhF-Sar-NH 2 ;

(SEQ ID NO: 70)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-OH;

(SEQ ID NO: 70)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-NH 2 ;

(SEQ ID NO: 166)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-

OH;

or

(SEQ ID NO: 166)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-

NH 2 .

11. The method of claim 1 , wherein the peptide is:

(SEQ ID NO: 43)

H-DMT-a-G-bhF-Sar-NH 2 ;

or

(SEQ ID NO: 43)

H-DMT-a-G-bhF-Sar-OH.

12. The method of claim 1 , wherein the peptide is:

(SEQ ID NO: 111)

H-DMT-a-G-bhF-N(Me)Ala-OH;

or

(SEQ ID NO: 183)

H-DMT-(D)Thr-G-bhF-N(Me)Ala-OH.

13. The method of claim 1 , wherein the peptide is:

(SEQ ID NO:83)

H-DMT-(D)Asp-G-bhF-Sar-OH;

or

(SEQ ID NO:83)

H-DMT-(D)Asp-G-bhF-Sar-NH2.

14. The method of claim 1 , wherein the peptide is:

(SEQ ID NO: 70)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-OH;

or

(SEQ ID NO: 70)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-NH 2 .

15. The method of claim 1 , wherein the peptide is:

(SEQ ID NO: 166)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-

OH;

or

(SEQ ID NO: 166)

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-

NH 2 .

16. The method of claim 1 , wherein the peptide is H-DMT-a-G-bhF-Sar-NH 2 (SEQ ID NO:43).

17. The method of claim 1 , wherein the peptide is H-DMT-(D)Thr-G-bhF-N(Me)Ala-OH (SEQ ID NO:183).

18. The method of claim 1 , wherein the peptide is H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-NH 2 (SEQ ID NO:70).