Stabilized melanocortin ligands

1. A non-naturally occurring melanocortin ligand comprising a melanocortin analog coupled to a degradation-resistant C-terminal extension and an N-terminal extension, the non-naturally occurring melanocortin ligand comprising Formula I:

Y 1 -Y 2 -Y 3 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -X 1 -X 2 -X 3   (Formula I)

wherein the melanocortin analog comprises R 1 to R 7 , wherein:

R 1 is absent or is selected from the group consisting of cysteine, norleucine, acetylated norleucine, acetylated cysteine, acetylated 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;

R 2 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;

R 3 is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, D-Nal(2′), L-Nal(2′), succinic acid, tButGly, Hyp(Bzl), Mamb, Oic, norleucine, Aba, β-alanine, and Tic;

R 4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2′), pCl-D-Phe, and (o-Phe)Phe;

R 5 is selected from the group consisting of arginine, homoarginine, ornithine, alanine, proline, Pip, Nip, Tic, Phg, Sar, and Azt;

R 6 is selected from D-tryptophan, L-tryptophan, D-Nal(2′), L-Nal(2′), Tic, and Bip;

R 7 is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, and 2,3-diamino-propionic acid;

wherein if R 3 is Aba, then R 4 is selected from the group consisting of D-Phe, D-Nal(2′), and pCl-D-Phe; and

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

wherein the degradation-resistant C-terminal extension comprises X 1 to X 3 :

X 1 is selected from the group consisting of cysteine, D-threonine, D-proline, and L-proline and a piperazin-2-one ring;

X 2 is absent or is selected from the group consisting D-threonine, D-proline, L-proline, and a piperazin-2-one ring;

X 3 is absent or is selected from the group consisting of D-threonine, and a piperazin-2-one ring; and

wherein when X 1 is cysteine, X 2 is not absent;

wherein the N-terminal extension comprises Y 1 to Y 3 :

Y 1 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, and L-proline;

Y 2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;

Y 3 is absent or is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring; and

wherein the melanocortin ligand 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 R7 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 or R 3 and R 7 when R 2 or R 3 is succinic acid and R 7 is 2,3-diamino-propionic acid.

2. A non-naturally occurring melanocortin ligand comprising a melanocortin analog coupled to a degradation-resistant C-terminal extension and an N-terminal extension, the non-naturally occurring melanocortin ligand comprising Formula II:

Y 1 -Y 2 -Y 3 -R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -X 1 -X 2 -X 3   (Formula II)

wherein the melanocortin analog comprises R 1 to R 9 , wherein:

R 1 is tyrosine;

R 2 is valine;

R 3 is selected from the group consisting of methionine, norleucine, cysteine, and L-penicillamine;

R 4 is selected from the group consisting of glycine, D-cysteine, L-cysteine, aspartic acid, and norleucine;

R 5 is selected from the group consisting of histidine, norleucine, proline, and Aib;

R 6 is selected from the group consisting of phenylalanine, D-Nal(2′), and L-Nal(2′);

R 7 is arginine;

R 8 is selected from the group consisting of tryptophan and D-Nal(2′); and

R 9 is absent or is selected from the group consisting of aspartic acid, cysteine, penicillamine, and lysine;

wherein the N-terminal extension comprises Y 1 to Y 3 :

Y 1 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, and L-proline;

Y 2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;

Y 3 is absent or is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline and a piperazin-2-one ring;

wherein the degradation-resistant C-terminal extension comprises X 1 to X 3 :

X 1 is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;

X 2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring; and

X 3 is absent or is selected from the group consisting of D-threonine, L-threonine, and a piperazin-2-one ring; and

wherein the melanocortin ligand is cyclized through a lactam side chain between R 4 and R 9 when R 4 is aspartic acid and R 9 is lysine.

3. The non-naturally occurring melanocortin ligand of claim 1 , wherein the melanocortin analog is an MC4 receptor agonist, an MC4 receptor antagonist, an MC3 receptor agonist, an MC3 receptor antagonist, and/or an MC5agonist.

4. The non-naturally occurring melanocortin ligand of claim 2 , wherein the melanocortin analog is an MC3 antagonist.

5. The non-naturally occurring melanocortin ligand of claim 1 , wherein D-phenylalanine is halogenated at the para position when R 4 is D-phenylalanine.

6. A pharmaceutical composition comprising the non-naturally occurring melanocortin ligand of claim 1 and a pharmaceutical salt.

7. The pharmaceutical composition of claim 6 , wherein any cardiovascular effects are diminished.

8. The pharmaceutical composition of claim 6 , wherein the non-naturally occurring melanocortin ligand is AcNle-c[Asp-Pro-D-Nal(2′)-Arg-Trp-Lys]-D-Thr-D-Pro-D-Thr.

9. A pharmaceutical composition comprising the non-naturally occurring melanocortin ligand of claim 2 and a pharmaceutical salt.

10. The pharmaceutical composition of claim 9 , wherein any cardiovascular effects are diminished.

11. The pharmaceutical composition of claim 9 , wherein the non-naturally occurring melanocortin ligand is Tyr-Val-Nle-c[Asp-Pro-D-Nal(2′)-Arg-Trp-Lys]-D-Thr-D-Pro-D-Thr.