Compositions and methods for modulating connexin hemichannels

1 . A method of modulating a hemichannel in a cell, tissue or organ exposed to stress, the method comprising contacting the stressed cell, tissue or organ with a therapeutically effective amount of Compound 1, wherein the contact is sufficient to close the hemichannel in the stressed cell, tissue or organ, and wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

2 . The method of claim 1 , wherein the method further comprises phosphorylating a tyrosine residue of connexin 43 (Cx 43).

3 . A method of preventing or treating tissue or organ stress in a mammal, the method comprising administering a therapeutically effective amount Compound 1, wherein the contact is sufficient to prevent or treat the stress in tissue or organ, and wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

4 . A method of increasing gap junction intracellular communication (GJIC) in a cell, tissue or organ, the method comprising administering a therapeutically effective amount of Compound 1, wherein the contact is sufficient to increase the GJIC in the cell, tissue or organ, and wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

5 . A method of treatment of burns comprising administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

6 . A method of treatment of thromboses comprising administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

7 . A method of treatment of respiratory and metabolic acidosis comprising administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

8 . A method of treatment of focal arrhythmia comprising administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

9 . A method of treating and preventing cell and tissue damage resulting from elevated levels of blood glucose comprising administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr-D-Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

10 . A method of treatment of chronic atrial fibrillation comprising administering to a patient in need of such treatment a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

11 . A method of cytoprotecting tissue or an organ of a mammal in need of such treatment, the method comprising administering a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

12 . A method of preventing or treating reperfusion injury in a mammal, the method comprising administering a therapeutically effective amount of Compound 1, wherein Compound 1 is defined as Ac- D -Tyr- D -Pro- D -4Hyp-Gly- D -Ala-Gly-NH 2 .

13 . The method of claim 3 or claim 14 , wherein the method further comprises phosphorylating a tyrosine residue of connexin 43 (Cx 43) and closing the hemichannel.

14 . A method of preventing or treating tissue or organ stress in a mammal, the method comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of compounds represented as Formula I or II as described above, wherein the contact is sufficient to prevent or treat the stress in tissue or organ, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

15 . A method of increasing gap junction intracellular communication (GJIC) in a cell, tissue or organ, the method comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of compounds represented as Formula I or II, wherein the contact is sufficient to increase the GJIC in the cell, tissue or organ, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

16 . A method of treatment of burns comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that blocks connexin hemichannel opening, wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

17 . A method of treatment of thromboses comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that blocks connexin hemichannel opening, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

18 . A method of treatment of respiratory and metabolic acidosis comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that blocks connexin hemichannel opening, wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

19 . A method of treatment of focal arrhythmia comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that blocks connexin hemichannel opening, wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

20 . A method of treating and preventing cell and tissue damage resulting from elevated levels of blood glucose comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that blocks connexin hemichannel opening, wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

21 . A method of treatment of chronic atrial fibrillation comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that blocks connexin hemichannel opening, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

22 . A method of treatment of epilepsia comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to Formula I or II that promotes connexin hemichannel opening, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

23 . A method of cytoprotecting tissue or an organ of a mammal in need of such treatment, the method comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of the compounds represented by Formula I or II, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

24 . The method of claim 11 or claim 23 , wherein the method further comprises exposing the tissue or organ of the mammal to ischemic conditions.

25 . The method of claim 24 , wherein the organ to be cytoprotected is associated with a fibrous capsule or bone.

26 . The method of claim 25 , wherein the organ is heart, kidney, brain, spinal cord or bone marrow.

27 . The method of claim 26 , wherein the heart has been subjected to an infarction and the ischemia is associated with myocardial cell swelling.

28 . The method of claim 27 , wherein the compound is Ac-Gly-Asn-Tyr-NH 2 (Compound 2).

29 . A method of preventing or treating reperfusion injury in a mammal, the method comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of the compounds represented by Formula I or II, and wherein Formula I is defined as follows:

wherein,

R1 represents H or acetyl (Ac)

R2 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R3 represents any amino acid sidechain,

R4 represents a sidechain of one of the amino acids Gly, Tyr, D-Tyr, Phe and D-Phe,

R5 represents OH or NH2,

and a, S, T, P and Q are integers and independently=0 or 1;

and salts thereof,

and wherein Formula II is defined as follows:

R1-X1-X2-X3-R2

wherein,

X1 is 0, Ala, Gly, β-Ala, Tyr, D-Tyr, Asp,

X2 is 0, Ala-Gly-T4c-Pro, Ala-Sar-Hyp-Pro, Ala-Asn, D-Asn-D-Ala, D-Asn, Gly, Ala, D-Ala,

β-Ala, Asn or,

X3 is Tyr, D-Tyr, Gly or Phe, and

R1 is H or Ac,

R2 is OH or NH2,

with the proviso that X1 and X2 are not both 0;

and salts thereof.

30 . The method of claim 12 or claim 29 , wherein the method further comprises exposing the heart of the mammal to infarct conditions and establishing coronary perfusion.

31 . The method of claim 30 , wherein the method further comprises administering a thrombolytic agent or providing coronary angioplasty to facilitate coronary perfusion into the infarcted heart.

32 . The method of claim 31 , wherein the compound is Ac-Gly-Asn-Tyr-NH 2 (Compound 2).