Compound and method for modulating opioid receptor activity

1. A compound having a structure of formula (I):

wherein

R 1 is H, C(NH)NH 2 , an amino acid, or a peptide;

X is OH, NH 2 , NHR 2 , NR 2 R 3 , an amino acid, or a peptide;

R 2 and R 3 are the same or different and selected from alkyl, alkylenearyl, or alkyleneheteroaryl;

each R 4 and R 5 is independently H or CH 3 ;

Z is an amino acid selected from the group consisting of 2-amino-2,3-dihydro-1H-indene-2-carboxylic acid (Aci); 2-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (Atc); 6-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene 6-carboxylic acid; cyclohexylalanine (Cha); cyclohexylglycine (Chg); homophenylalanine (Hfe); 1-naphthylalanine (1-Nal); 2-naphthylalanine (2-Nal); 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); and octahydro-1H-indole-2-carboxylic acid (Oic);

n is 0, 1, 2, 3, or 4;

with the proviso that X is not NH 2 when R 1 is H, each R 4 is H, each R 5 is CH 3 , Z is Aci, and n is 2;

or a pharmaceutically acceptable salt, ester or solvate thereof.

2. The compound of claim 1 , wherein R 1 is arginine.

3. The compound of claim 1 or claim 2 , wherein X is an amino acid selected from the group consisting of serine, threonine, arginine, homoarginine, and modified residues thereof.

4. The compound of claim 3 , wherein X is a modified residue selected from the group consisting of serine, threonine, arginine, and homoarginine, and wherein the modified residue is substituted with one or more of NH 2 , OH, alkyl substituents, alkylenearyl substituents, alkyloxy substituents, and/or alkylenearyloxy substituents.

5. The compound of claim 4 , wherein X is a modified arginine or homoarginine residue having the structure:

wherein

m is 1 or 2;

R 6 is selected from the group consisting of NH 2 , OH, and OR 9 ; and

R 7 , R 8 , and R 9 are individually selected from the group consisting of alkyl substituents and alkylenearyl substituents.

6. The compound of claim 1 , wherein R 1 and/or X is a glycosylated amino acid or a glycosylated peptide.

7. The compound of claim 1 , wherein X is a glycosylated amino acid or glycosylated peptide comprising a glycosyl group selected from the group consisting of alpha and beta anomers of cellobiose, D-glucose, fucose, lactose, maltose, maltotriose, melibiose, and xylose.

8. The compound of claim 1 , wherein R 1 and/or X is a cell penetrating peptide.

9. The compound of claim 1 , wherein each R 4 is H.

10. The compound of claim 1 , wherein one R 4 is H and one R 4 is CH 3 .

11. The compound of claim 1 , wherein each R 4 is CH 3 .

12. The compound of claim 1 , wherein each R 5 is H.

13. The compound of claim 1 , wherein one R 5 is H and one R 4 is CH 3 .

14. The compound of claim 1 , wherein one R 5 is H and one R 5 is CH 3 .

15. The compound of claim 1 , wherein each R 5 is CH 3 .

16. The compound of claim 1 having a structure:

17. The compound of claim 1 having a structure:

18. The compound of claim 1 having a structure:

19. The compound of claim 1 having a structure:

20. The compound of claim 1 having a structure:

21. The compound of claim 1 having a structure:

22. The compound of claim 1 having a structure:

23. The compound of claim 1 having a structure:

24. The compound of claim 1 having a structure:

25. The compound of claim 1 having a structure:

26. The compound of claim 1 having a structure:

27. The compound of claim 1 having a structure:

28. The compound of claim 1 having a structure:

29. The compound of claim 1 having a structure:

30. The compound of claim 1 having a structure:

31. The compound of claim 1 having a structure:

32. The compound of claim 1 conjugated to an entity that enhances the half life of the compound, enhances cellular uptake of the compound, and/or enhances transport across the blood-brain barrier.

33. The compound of claim 32 , wherein the compound is conjugated to a water soluble polymer.

34. The compound of claim 32 , wherein the compound is conjugated to albumin, an antibody or fragment thereof, or a proline-alanine-serine multimer (PASylation).

35. The compound of claim 1 , wherein the compound is a mu-opioid receptor (MOR) agonist and a delta-opioid receptor (DOR) antagonist.

36. The compound of claim 1 , wherein the compound displays substantially equivalent binding affinity for MOR and DOR.

37. The compound of claim 1 , wherein the compound binds MOR and DOR with an affinity at least 100 times greater than the compound binds kappa-opioid receptor (KOR).

38. A method of modulating the activity of MOR and/or DOR, the method comprising exposing a MOR and/or a DOR to the compound of claim 1 .

39. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

40. The composition of claim 39 further comprising one or more therapeutic agents.

41. A method of treating pain in a subject, the method comprising administering to the subject the composition of claim 39 in an amount sufficient to induce analgesia.

42. The method of claim 41 , wherein administration of the composition of claim 39 attenuates physical dependence or tolerance associated with opioid use.

43. A method for treating a mu-opioid receptor (MOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 39 in an amount sufficient to ameliorate the disorder.

44. A method for treating a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 39 in an amount sufficient to ameliorate the disorder.

45. A method for treating a mu-opioid receptor (MOR) mediated disorder and a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 39 in an amount sufficient to ameliorate the disorder.

46. The method of claim 41 , wherein the composition is administered intrathecally, intravenously, subcutaneously, intramuscularly, or orally.

47. The method of claim 41 , further comprising administering to the subject an additional therapeutic agent and/or an agent that facilitates transport across the blood-brain barrier.

48. A method of modulating the activity of MOR and/or DOR, the method comprising exposing a MOR and/or a DOR to the compound of claim 25 .

49. A composition comprising the compound of claim 25 and a pharmaceutically acceptable carrier.

50. The composition of claim 49 further comprising one or more therapeutic agents.

51. A method of treating pain in a subject, the method comprising administering to the subject the composition of claim 49 in an amount sufficient to induce analgesia.

52. The method of claim 51 , wherein administration of the composition of claim 49 attenuates physical dependence or tolerance associated with opioid use.

53. A method for treating a mu-opioid receptor (MOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 49 in an amount sufficient to ameliorate the disorder.

54. A method for treating a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 49 in an amount sufficient to ameliorate the disorder.

55. A method for treating a mu-opioid receptor (MOR) mediated disorder and a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 49 in an amount sufficient to ameliorate the disorder.

56. A method of modulating the activity of MOR and/or DOR, the method comprising exposing a MOR and/or a DOR to the compound of claim 31 .

57. A composition comprising the compound of claim 31 and a pharmaceutically acceptable carrier.

58. The composition of claim 57 further comprising one or more therapeutic agents.

59. A method of treating pain in a subject, the method comprising administering to the subject the composition of claim 57 in an amount sufficient to induce analgesia.

60. The method of claim 59 , wherein administration of the composition of claim 57 attenuates physical dependence or tolerance associated with opioid use.

61. A method for treating a mu-opioid receptor (MOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 57 in an amount sufficient to ameliorate the disorder.

62. A method for treating a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 57 in an amount sufficient to ameliorate the disorder.

63. A method for treating a mu-opioid receptor (MOR) mediated disorder and a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 57 in an amount sufficient to ameliorate the disorder.