Methods for the treatment of central nervous system (CNS) disorders and mood disorders

Patent metadata

Field	Value
Publication number	US-9821023-B2
Application number	US-201514943885-A
Country	US
Kind code	B2
Filing date	Nov 17, 2015
Priority date	Jun 10, 2014
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Methods of treating a central nervous system (CNS) disorder or mood disorder in a subject in need of such treatment are described. A therapeutically effective amount of a composition comprising a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier is administered to the subject. The MC5R peptide ligand is a selective MC5R antagonist, in which administration thereof to the subject can treat the CNS disorder or mood disorder with clinical improvement observed in a relatively short time.

First claim

What is claimed is:

1. A method of treating a central nervous system (CNS) disorder in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a composition comprising a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier, wherein the MC5R peptide ligand is represented by Formula 1:
R 1 -Nle 4 -c[Xaa 5 -Yaa 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Zaa 10 ]-R 2

wherein R 1 is an acetyl, a glycosylated amino acid, or —CO—(CH 2 ) n CH 3 , wherein n ranges from 1 to 6,
wherein R 2 is an —CONH 2 , —COOH, or —CH 2 OH,
wherein Xaa, Yaa, and Zaa are each a natural amino acid or an unnatural amino acid,
wherein D-Nal(2′) 7 is N-methylated,
wherein the CNS disorder is a mood disorder or Bell's Palsy, and
wherein administration of the composition treats the CNS disorder in the subject such that clinical improvement is observed in about 1 to 14 days.

2. The method of claim 1 , wherein the subject is a mammal, wherein the mammal is a human.

3. The method of claim 1 , wherein MC5R peptide ligand is an antagonist of melanocortin 5 receptor.

4. The method of claim 1 , wherein the MC5R peptide ligand is administered in a dosage of about 0.001 mg/kg to 100 mg/kg of body weight, wherein the composition is administered twice a day, daily, or every other day.

5. The method of claim 1 , wherein Xaa is selected from a group consisting of Asp, Glu, and Abu.

6. The method of claim 1 , wherein Yaa is selected from a group consisting of His, Pro, octahydroindole-2-carboxylic acid, indoline-2-carboxyic acid, tetrahydro-isoquinoline-3-carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, 2-aminoindane-2-carboxylic acid, and 1-aminocyclopropane carboxylic acid.

7. The method of claim 1 , wherein Zaa is selected from a group consisting of Lys, Orn, and diaminobutyric acid.

8. The method of claim 1 , wherein the glycosylated amino acid comprises a saccharide linked to a natural amino acid, wherein the natural amino acid is Ser, Thr, Tyr, Asn or Gln, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.

9. The method of claim 1 , wherein Xaa is linked to Zaa via a carha, lactam, disulfide, thioether, or succinic linker, thereby forming a cyclic peptide.

10. A method of treating a mood disorder in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a composition comprising a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier, wherein the MC5R peptide ligand is represented by Formula 1:
R 1 -Nle 4 -c[Xaa 5 -Yaa) 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Zaa 10 ]-R 2

wherein R 1 is an acetyl, a glycosylated amino acid, or —CO—(CH 2 ) n CH 3 , wherein n ranges from 1 to 6,
wherein R 2 is an —CONH 2 , —COOH, or —CH 2 OH,
wherein Xaa is a natural amino acid or an unnatural amino acid with a proviso that the Xaa is not Asp, wherein Yaa is a natural amino acid or an unnatural amino acid with a proviso that Yaa is not His, and Wherein Zaa is a natural amino acid or an unnatural amino acid with a proviso that Zaa is not Lys,
wherein D-Nal(2′) 7 is N-methylated, and
wherein administration of the composition treats the mood disorder in the subject such that clinical improvement is observed in about 1 to 14 days.

11. The method of claim 10 , wherein the subject is a mammal, wherein the mammal is a human.

12. The method of claim 10 , wherein the MC5R peptide ligand is an antagonist of MC5R.

13. The method of claim 10 , wherein the MC5R peptide ligand is administered in a dosage of about 0.001 mg/kg to 100 mg/kg of body weight, wherein the composition is administered twice a day, daily, or every other day.

14. The method of claim 10 , wherein the mood disorder is a depressive disorder or an anxiety disorder.

15. The method of claim 14 , wherein administration of the composition is effective to evoke at least one of a psychostimulating effect, an anxiolytic effect, or an antidepressant effect.

16. The method of claim 10 , wherein Xaa is a Glu or Abu.

17. The method of claim 10 , wherein Yaa is selected from a group consisting of Pro, octahydroindole-2-carboxylic acid, indoline-2-carboxyic acid, tetrahydro-isoquinoline-3-carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 1- amino-1-cyclohexane carboxylic acid,2-aminoindane-2-carboxylic acid, and 1-aminocyclopropane carboxylic acid.

18. The method of claim 10 , wherein Zaa is an Orn or diaminobutyric acid.

19. The method of claim 10 , wherein the glycosylated amino acid comprises a saccharide linked to a natural amino acid, wherein the natural amino acid is Ser, Thr, Tyr, Asn or Gln, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.

20. The method of claim 10 , wherein Xaa is linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker, thereby forming a cyclic peptide.

Assignees

• Univ Arizona

Inventors

• Hruby Victor J
• Cai Minying

Classifications

• C07K14/685

  Alpha-melanotropin · CPC title

• A61K47/24

  containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids · CPC title

• C07K14/723

  G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor · CPC title

• A61K9/7084

  Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches · CPC title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title