Melanocortin analogs having enhanced activity and transport

1. A non-naturally occurring melanocortin analog comprising a metabolically stable C-terminal extension that minimizes or reduces side effects and that facilitates traversal of epithelium membranes, blood-brain barrier membranes, or both membranes, comprising:

the sequence according to Formula I: X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 Y 1 Y 2 Y 3 , wherein:

the melanocortin analog residues comprise:

R1 is absent or is selected from the group consisting of cysteine, norleucine, acetylated norleucine, acetylated cysteine, methylated D -phenylalanine, succinic acid, o-phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;

R2 is absent or is selected from the group consisting of proline, aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;

R3 is selected from the group consisting of histidine, histidine methylated at positions 1 or 3 , D -proline, L -proline and succinic acid;

R4 is selected from the group consisting of histidine, D-phenylalanine, L -phenylalanine, D -Nal(2′), pCl- D -Phe, and (o-Phe)Phe;

R5 is selected from the group consisting of arginine, homoarginine, ornithine, alanine, proline, Pip, Nip, Tic, Phg, Sar, and Azt;

R6 is selected from D -tryptophan, L -tryptophan, D -Nal(2′), L -Nal(2′), Tic, and Bip;

R7 is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, and 2,3-diamino-propionic acid;

wherein if R2 is an n-pentanoyl group or an n-hexanoyl group, then R 1 , X 1 , X 2 and X 3 are absent;

X 1 is selected from the group consisting of D-cysteine, L-cysteine, D -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, β-alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring;

X 2 is absent or is selected from the group consisting of D -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, β-alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring; and

X 3 is absent or is selected from the group consisting of D -cysteine, L -cysteine, D -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring;

Y 1 is selected from the group consisting of D -alanine, L -alanine, D -valine, L -valine, D -leucine, L -leucine, D -isoleucine, an L -isoleucine;

Y 2 is selected from the group consisting of D -proline and L -proline; and

Y 3 is absent;

the melanocortin analog is cyclized through a moiety selected from the group consisting of:

a disulfide bond between R 1 or R 2 and R 7 or X 1 when R 1 or R 2 is cysteine and R 7 or X 1 is cysteine;

a lactam bridge between R 1 and R 7 when R 1 is norleucine and R 7 is glutamic acid;

a side-chain lactam bridge between R 2 and R 7 when R 2 is glutamic acid or aspartic acid and R 7 is lysine;

a lactam closure between R 1 and R 7 when R 1 is succinic acid or o-phthalic acid and R 7 is lysine; and

a lactam closure between R 2 and R 7 when R 2 is succinic acid and R 7 is 2,3-diamino-propionic acid;

the N-terminus is modified by acylation; and

the C-terminus is modified by amidation.

2. A non-naturally occurring melanocortin analog comprising any one of the sequences of SEQ ID NOs: 21, 30, 31, 32, 33, 66, 67, 68, 69, 90, 91, 92, 93, 118, 119, 120, 121, 154, 155, 156, 157, 178, 179, 180 or 181.

3. The non-naturally occurring melanocortin analog of claim 1 , wherein the melanocortin analog is effective in modulating one or more of cachexia, lethargy, appetite, sleep, arousal, libido, locomotion, cardiovascular anomalies, vasodilatation, hypertension, hypotension, sodium regulation, pain, pain perception, increasing endogenous opioid activity, or decreasing opioid tolerance.

4. A pharmaceutical composition comprising the non-naturally occurring melanocortin analog of claim 1 .

5. The pharmaceutical composition of claim 4 , further comprising a pharmaceutical salt.

6. The pharmaceutical composition of claim 4 , wherein the side effects are reduced compared to a natural melanocortin.

7. A method of treating a disorder in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog of claim 1 .

8. The method of claim 7 , wherein the administration route is intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or orally.

9. The method of claim 8 , wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier.

10. The method of claim 7 , wherein the side effects are reduced compared to a natural melanocortin.

11. A kit for treating cachexia in a subject in need thereof, comprising individual containers containing the pharmaceutical composition of claim 4 , a device for administering the pharmaceutical composition, a reagent for diluting the pharmaceutical composition, and instructions for use.

12. The non-naturally occurring melanocortin analog of claim 1 , comprising the sequence of SEQ ID NO: 21.

13. A pharmaceutical composition comprising the non-naturally occurring melanocortin analog of claim 1 or a pharmaceutically acceptable salt thereof and, optionally, one or more pharmaceutically acceptable carriers.