[go: up one dir, main page]

WO2017066769A1 - Compositions et procédés de traitement de troubles du système nerveux central (snc) et de troubles de l'humeur - Google Patents

Compositions et procédés de traitement de troubles du système nerveux central (snc) et de troubles de l'humeur Download PDF

Info

Publication number
WO2017066769A1
WO2017066769A1 PCT/US2016/057364 US2016057364W WO2017066769A1 WO 2017066769 A1 WO2017066769 A1 WO 2017066769A1 US 2016057364 W US2016057364 W US 2016057364W WO 2017066769 A1 WO2017066769 A1 WO 2017066769A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
composition
mc5r
natural amino
peptide ligand
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2016/057364
Other languages
English (en)
Inventor
Victor J. Hruby
Minying Cai
Horst Kessler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Arizona
Arizona's Public Universities
Original Assignee
University of Arizona
Arizona's Public Universities
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/943,606 external-priority patent/US20170022252A1/en
Priority claimed from US14/943,936 external-priority patent/US9814755B2/en
Priority claimed from US14/943,885 external-priority patent/US9821023B2/en
Application filed by University of Arizona, Arizona's Public Universities filed Critical University of Arizona
Priority to US15/768,340 priority Critical patent/US10550157B2/en
Publication of WO2017066769A1 publication Critical patent/WO2017066769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to N-methylated variations of a cyclic peptide and analogues thereof that are modulators for MC5R.
  • the present invention relates to compositions and methods of treating central nervous system (CNS) disorders and mood disorders with selective melanocortin 5 receptor (MC5R) antagonists. BACKGROUND OF THE INVENTION
  • Central nervous system (CNS) disorders are diseases that can affect the brain or spinal cord.
  • the CNS disorders may be caused by trauma, infections, degeneration, structural defects, tumors, blood flow disruption, autoimmunity, or strokes.
  • CNS medications include analgesics, anticonvulsants, antipsychotics, sedatives, and tranquilizers.
  • CNS medications have the potential for developing tolerance, dependence, or addiction.
  • Mood disorders such as depression and anxiety disorders, are some of the most common mental illnesses. Although the two are different, depression and anxiety can occur together and can have similar treatments.
  • Melanocortin receptors are a family of five receptor compounds of the melanocortin receptor system. Prior to the invention, it has been difficult to target the receptors independently of one another. The key difference between the present invention and similar compounds is that the present invention is specific to individual types of melanocortin receptors, specifically to MC5R.
  • An N-methylated form of a cyclic peptide, Ac-Nle 4 -c[Asp 5 , D-Nal(2’ )7 , Lys 10 ] ⁇ -MSH(4-10)-NH 2 (SHU9119) and analogues thereof can antagonize MC5R.
  • the subject disclosure relates to compositions for use and methods of treating a central nervous system (CNS) disorder or a mood disorder.
  • the composition may comprise a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier.
  • M5R melanocortin 5 receptor
  • the composition is administered in a subject in need of such treatment.
  • the MC5R peptide ligand is according to Formula 1:
  • R 1 may be an acetyl, a glycosylated amino acid,–CO- (CH 2 ) n CH 3 , or–CO-(CH 2 ) n CF 3 , wherein n ranges from 1 to 6.
  • R 2 may be an amide (e.g.–CONH 2 ),–COOH, or–CH 2 OH.
  • Xaa is a natural amino acid or an unnatural amino acid
  • Yaa is a natural amino acid or an unnatural amino acid
  • Zaa is a natural amino acid or an unnatural amino acid.
  • the MC5R peptide ligand is an antagonist of MC5R.
  • the MC5R may be present in the central nervous system (CNS), but its function in this location is not completely understood. Without wishing to limit the invention to a particular theory or mechanism, since the MC5R peptide ligand is a selective MC5R antagonist, then the MC5R peptide ligand may be potentially therapeutic for treating the CNS disorder or mood disorder. None of the presently known prior references or work has the unique inventive technical feature of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1A shows a structure of SHU 9119. The two arrows indicate the sites of N- methylation of the backbone NHs to form one embodiment of a MC5R modulator.
  • FIG. 1B shows a non-limiting example of a structure of an analogue that has been N-methylated at the sites shown in FIG.1A. DESCRIPTION OF PREFERRED EMBODIMENTS
  • Tic tetrahydro-isoquinoline-3-carboxylic Acid refers to the twenty amino acids that are found in nature, i.e. occur naturally.
  • the natural amino acids are as follows: alanine, arginine, glycine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, serine, threonine, histidine, lysine, methionine, proline, valine, isoleucine, leucine, tyrosine, tryptophan, and phenylalanine. This application adheres to the IUPAC rules of standard abbreviations for amino acids.
  • the term“unnatural amino acids” refers to amino acids that are not naturally encoded or found in the genetic code of any organisms. Typically, the unnatural amino acids are different from the twenty naturally occurring amino acids in their side chain functionality.
  • the term“antagonist” refers to compound that diminishes a response. The antagonist binds to the same site as the endogenous compound and diminishes or blocks the signal generated by the endogenous agent.
  • the term“N-methylation” refers to a form of alkylation wherein a methyl group, CH 3 , replaces the hydrogen atom of the NH moiety in the backbone amide NHs of peptides.
  • the term“NMe” preceding any three-letter abbreviation for an amino acid denotes the N-methylated form of the amino acid.
  • the term“c” or“cyclo” means cyclic, i.e. a cyclic peptide.
  • “glycosylated” is defined as a saccharide (or sugar) covalently attached, i.e. linked, to an amino acid. Specifically, the saccharide is linked to the side- chain of the amino acid.
  • the glycosylated amino acid may comprise a saccharide O-linked to a natural amino acid.
  • the saccharide is attached to the hydroxyl group of the side-chain of the amino acid, such as Ser, Thr, or Tyr.
  • glycosylated peptides include, but are not limited to, glucosylated Serine, glucosylated Threonine, and lactosylated Serine.
  • the glycosylated amino acid may comprise a saccharide N-linked to a natural amino.
  • the saccharide is attached to the amine group of the side-chain of the amino acid, such as Asn or Lys.
  • the saccharide may be a mono-, di-, tri- and poly- saccharides.
  • saccharides include, but are not limited to, glucose, fructose, galactose, cellobiose, and lactose.
  • glycosylation may increase the ability of the peptide to cross a blood brain barrier (BBB) as compared to a peptide lacking the glycosylation.
  • BBB blood brain barrier
  • “clinical improvement” may refer to a noticeable reduction or cessation of the symptoms of a disorder.
  • antigenital effect is used in the conventional sense. It is associated with a reversal of or a reduction in the severity of a depressed mood or state of mind.
  • the term“anxiolytic effect” is used in the conventional sense.
  • psychostimulating effect is associated in an increase or improvement in the overall level of mental activity. It is related to patients exhibiting nervous behavior, or having unpleasant feelings of dread, or lacking energy, drive and desire, or lacking concentration and memory. Common psychostimulating effects may include, but are not limited to, enhanced alertness, awareness, wakefulness, endurance, productivity, motivation, increased arousal, and locomotion (i.e. movement or increased energy). The psychostimulants may also be capable of improving mood and relieving anxiety, and can even induce feelings of euphoria.
  • the present invention features a composition for use in treating a central nervous system (CNS) disorder or a mood disorder.
  • the composition may comprise a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier.
  • M5R melanocortin 5 receptor
  • the MC5R peptide ligand is according to Formula 1:
  • R 1 may be an acetyl, a glycosylated amino acid,–CO- (CH 2 ) n CH 3 , or–CO-(CH 2 ) n CF 3 , wherein n ranges from 1 to 6.
  • R 2 may be an amide (e.g.–CONH 2 ),–COOH, or–CH 2 OH.
  • Xaa is a natural amino acid or an unnatural amino acid
  • Yaa is a natural amino acid or an unnatural amino acid
  • Zaa is a natural amino acid or an unnatural amino acid.
  • the MC5R peptide ligand is an antagonist of MC5R.
  • Xaa may be Asp, Glu or 2-aminobutyric acid.
  • Yaa may be selected from a group consisting of His, Pro, octahydroindole- 2-carboxylic acid, indoline-2-carboxylic acid, tetrahydro-isoquinoline-3-carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 2- aminoindane-2-carboxylic acid, and 1-aminocyclopropane carboxylic acid.
  • Zaa may be Lys, ornithine or diaminobutyric acid.
  • the composition for use in treating a central nervous system (CNS) disorder or a mood disorder may comprise the following melanocortin 5 receptor (MC5R) peptide ligand:
  • the glycosylated amino acid may comprise a saccharide linked to a natural amino acid, such as Ser, Thr, Tyr, Asn or Gln.
  • the saccharide may be a monosaccharide, a disaccharide, or an oligosaccharide.
  • the saccharide may be glucose, fructose, or lactose.
  • the glycosylated amino acid may comprise a saccharide O-linked to a natural amino acid, such as Ser, Thr, or Tyr.
  • the glycosylated amino acid may comprise a saccharide N-linked to a natural amino acid, such Asn or Lys.
  • Xaa may be linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker, thereby forming a cyclic peptide.
  • the MC5R peptide ligand may comprise a 23- to 27-membered ring.
  • the composition for use is administered to a subject who has been diagnosed with the CNS disorder or mood disorder.
  • the disorder is a CNS disorder.
  • the disorder is a mood disorder, such as a depressive disorder or an anxiety disorder.
  • the disorder may be a combination of CNS and mood disorders.
  • a mood disorder may arise from or be symptom of the CNS disorder.
  • the composition can be administered once daily or twice daily.
  • the composition can be administered at least once daily, at least once every other day, or at least once weekly.
  • the composition is administered at a daily dose ranging from about 0.001 mg/kg to 100 mg/kg of body weight.
  • the composition is administered intranasally, intravenously, transdermally, or orally.
  • the composition can treat the CNS disorder or the mood disorder such that clinical improvement is observed in about 1 to 14 days, for instance, in 1-7 says, or 7-14 days.
  • the composition may be effective to evoke at least one of a psychostimulating effect, an anxiolytic effect, or an antidepressant effect.
  • the present invention features a composition for use in treating a CNS disorder or a mood disorder in a subject, comprising determining if the subject has the CNS disorder or a mood disorder, and administering a therapeutically effective amount of the composition to the subject if it is determined that the subject has the CNS disorder or a mood disorder.
  • the composition for use may comprise a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier.
  • M5R melanocortin 5 receptor
  • the MC5R peptide ligand may be according to 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 (SEQ NO.1) [0048]
  • R 1 may be an acetyl, a glycosylated amino acid,–CO- (CH 2 ) n CH 3 , or–CO-(CH 2 ) n CF 3 , wherein n ranges from 1 to 6.
  • R 2 may be an amide (e.g.–CONH 2 ),–COOH, or–CH 2 OH.
  • Xaa is a natural amino acid or an unnatural amino acid
  • Yaa is a natural amino acid or an unnatural amino acid
  • Zaa is a natural amino acid or an unnatural amino acid.
  • the MC5R peptide ligand is an antagonist of MC5R.
  • Xaa may be Asp, Glu or 2-aminobutyric acid.
  • Yaa may be selected from a group consisting of His, Pro, octahydroindole- 2-carboxylic acid, indoline-2-carboxylic acid, tetrahydro-isoquinoline-3-carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 2- aminoindane-2-carboxylic acid, and 1-aminocyclopropane carboxylic acid.
  • Zaa may be Lys, ornithine or diaminobutyric acid.
  • the composition for use in treating a CNS disorder or a mood disorder in a subject may comprise the following melanocortin 5 receptor (MC5R) peptide ligand:
  • the glycosylated amino acid may comprise a saccharide linked to a natural amino acid, such as Ser, Thr, Tyr, Asn or Gln.
  • the saccharide may be a monosaccharide, a disaccharide, or an oligosaccharide.
  • the saccharide may be glucose, fructose, or lactose.
  • the glycosylated amino acid may comprise a saccharide O-linked to a natural amino acid, such as Ser, Thr, or Tyr. In another embodiment, the glycosylated amino acid may comprise a saccharide N-linked to a natural amino acid, such Asn or Lys.
  • Xaa may be linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker, thereby forming a cyclic peptide.
  • the MC5R peptide ligand may comprise a 23- to 27-membered ring.
  • the composition can be administered once daily or twice daily.
  • the composition can be administered at least once daily, at least once every other day, or at least once weekly. In some embodiments, the composition is administered at a daily dose ranging from about 0.001 mg/kg to 100 mg/kg of body weight. In other embodiments, the composition is administered intranasally, intravenously, transdermally, or orally. In preferred embodiments, the composition for use in the treatment resulted in clinical improvement of the depressive disorder or anxiety disorder that is observed in about 1 to 14 days, such as, for example, about 1 to 7 days or about 7 to 14 days.
  • M5R melanocortin 5 receptor
  • R 1 is an acetyl, a glycosylated amino acid,–CO-(CH 2 ) n CH 3 , or–CO-(CH 2 ) n CF 3 , with n ranging from 1 to 6.
  • R 2 is an amide (e.g.–CONH 2 ),–COOH, or–CH 2 OH.
  • Xaa is a natural amino acid or an unnatural amino acid
  • Yaa is a natural amino acid or an unnatural amino acid
  • Zaa is a natural amino acid or an unnatural amino acid, with the proviso that Xaa is not Asp, Yaa is not His, and Zaa is not Lys concurrently.
  • the glycosylated amino acid may comrpise a saccharide O-linked to a natural amino acid, such as Ser, Thr, or Tyr.
  • the glycosylated amino acid may comprise a saccharide N-linked to a natural amino acid, such as Asn or Lys.
  • the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide, such as, for example, glucose, fructose, or lactose.
  • Xaa may be Glu or 2-aminobutyric acid.
  • Yaa may be selected from a group consisting of Pro, octahydroindole-2- carboxylic acid, indoline-2-carboxylic acid, tetrahydro-isoquinoline-3-carboxylic acid, 1- amino-1-cyclohexane carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 2- aminoindane-2-carboxylic acid, and 1-aminocyclopropane carboxylic acid.
  • Zaa may be ornithine or diaminobutyric acid.
  • the MC5R peptide ligand is a cyclised peptide formed when Xaa is linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker. In other embodiments, the MC5R peptide ligand comprises a 23 to 27-membered ring.
  • the present invention features a method of treating a central nervous system (CNS) disorder or a mood disorder in a subject in need thereof.
  • the method may comprise administering to the subject a therapeutically effective amount of a composition comprising a melanocortin 5 receptor (MC5R) peptide ligand in a pharmaceutically acceptable carrier.
  • the MC5R peptide ligand may be according to Formula 1:
  • R 1 is an acetyl, a glycosylated amino acid, –CO- (CH 2 ) n CH 3 , or–CO-(CH 2 ) n CF 3 , with n ranging from 1 to 6.
  • R 2 is an amide (e.g.–CONH 2 ),–COOH, or–CH 2 OH.
  • Xaa can be a natural amino acid or an unnatural amino acid
  • Yaa can be a natural amino acid or an unnatural amino acid
  • Zaa can be a natural amino acid or an unnatural amino acid.
  • MC5R peptide ligand is an antagonist of MC5R.
  • Xaa may be Asp, Glu or 2-aminobutyric acid.
  • Yaa may be selected from a group consisting of His, Pro, octahydroindole- 2-carboxylic acid, indoline-2-carboxylic acid, tetrahydro-isoquinoline-3-carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, 1-amino-1-cyclopentane carboxylic acid, 2- aminoindane-2-carboxylic acid, and 1-aminocyclopropane carboxylic acid.
  • Zaa may be Lys, ornithine or diaminobutyric acid.
  • the glycosylated amino acid may comprise a saccharide linked to a natural amino acid, such as Ser, Thr, Tyr, Asn or Gln.
  • the saccharide may be a monosaccharide, a disaccharide, or an oligosaccharide.
  • the saccharide may be glucose, fructose, or lactose.
  • the glycosylated amino acid may comprise a saccharide O-linked to a natural amino acid, such as Ser, Thr, or Tyr.
  • the glycosylated amino acid may comprise a saccharide N-linked to a natural amino acid, such Asn or Lys.
  • Xaa may be linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker, thereby forming a cyclic peptide.
  • the MC5R peptide ligand may comprise a 23- to 27-membered ring.
  • the method of treating a CNS disorder or a mood disorder in a subject in need of such treatment may comprise administering to the subject a therapeutically effective amount of a composition comprising:
  • the subject is a mammal, such as a human.
  • the composition may be administered at a daily dose ranging from about 0.001 mg/kg to 100 mg/kg of body weight.
  • the composition may be administered once daily or twice daily.
  • the composition may be administered at least once daily, at least once every other day, or at least once weekly.
  • the composition may be administered intranasally, intravenously, transdermally, or orally.
  • the MC5R peptide ligand is a selective MC5R antagonist
  • the MC5R peptide ligand may be potentially therapeutic for treating the CNS disorder or mood disorder.
  • the disorder is treated such that clinical improvement may be observed in about 1 to 14 days, for instance, in about 1 to 7 days or about 1 to 14 days.
  • administration of the composition may be effective to evoke at least one of a psychostimulating effect, an anxiolytic effect, or an antidepressant effect.
  • the composition may be administered in a dosage of about 0.001 mg/kg to 100 mg/kg of body weight.
  • the dosage may range from about 0.001 mg/kg to 1 mg/kg of body weight, or about 1 mg/kg to 10 mg/kg of body weight, or about 10 mg/kg to 20 mg/kg of body weight, or about 20 mg/kg to 30 mg/kg of body weight, or about 30 mg/kg to 40 mg/kg of body weight, or about 50 mg/kg to 60 mg/kg of body weight, or about 60 mg/kg to 70 mg/kg of body weight, or about 70 mg/kg to 80 mg/kg of body weight, or about 80 mg/kg to 90 mg/kg of body weight, or about 90 mg/kg to 100 mg/kg of body weight.
  • Alternative embodiments for treating the CNS disorder or mood disorder in the subject may include administering the composition is combination with a non-pharmacological treatment.
  • non-pharmacological treatments may include, but are not limited to, is psychotherapy, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, acupuncture, hypnosis, meditation, an exercise regimen, and administration of naturopathic herbs and supplements.
  • the N-terminal modification refers to the modification of the NH 2 at the N-terminus, resulting in R 1 being linked to the NH moiety. N-terminal modifications are known to one of ordinary skill in the art.
  • acetylation of the N-terminal results in R 1 being an acetyl.
  • R 1 may be a glycosylated amino acid.
  • the glycosylated amino acid may comprise a saccharide O-linked to a natural amino acid.
  • the saccharide is attached to the hydroxyl group of the side-chain of the amino acid, such as Ser, Thr, or Tyr.
  • the glycosylated amino acid may comprise a saccharide N-linked to a natural amino.
  • the saccharide is attached to the amine group of the side-chain of the amino acid, such as Asn or Lys.
  • saccharides include, but are not limited to, glucose, fructose, and lactose.
  • R 1 may be –CO-(CH 2 ) n CH 3 or –CO-(CH 2 ) n CF 3 .
  • “n” can range from 1 to 6.
  • N- terminal modifications may play a role in stability, protein folding, cellular attachment, and function modulation of the MC5R peptide ligand.
  • the C-terminal modification refers to the modification of the carboxyl moiety at the C-terminus.
  • C-terminal modifications are known to one of ordinary skill in the art.
  • R 2 can be an amide (e.g.–CONH 2 ) or– CH 2 OH.
  • C- terminal modifications such as amidation, can enhance the biological activity of the peptide ligand, increase the ligand’s stability, efficacy, and ability to enter cells, as well as increase its ability to resist enzymatic degradation.
  • Xaa may be a natural amino acid or an unnatural amino acid.
  • Xaa may be the natural amino acid Asp or Glu, or the unnatural amino acid Abu.
  • Yaa may be a natural amino acid such as His or Pro, or an unnatural amino acid such as Oic, Ioc, Tic, Cpe, Che, Aic, and Acpc.
  • the Yaa modification can provide for a stable ⁇ turn-like structure and improved potency of the MC5R peptide ligand.
  • Zaa may be a natural amino acid such as Lys, or an unnatural amino acid such as Orn, and Dab.
  • a side-chain of the amino acid in the MC5R peptide ligand may be halogenated.
  • the side-chain of Phe can be halogenated.
  • His cannot be halogenated.
  • the side-chain of (NMe)D-Nal(2’) or Trp in the cyclic peptide may be para-, meta-, or ortho- halogenated or di-halogenated.
  • a side-chain of the amino acid may be glycosylated.
  • the side-chain of Lys in the cyclic peptide may be glycosylated.
  • R 1 , R 2 , Xaa, Yaa, and Zaa are non-limiting.
  • Xaa, Yaa, and Zaa can be any natural amino acid or unnatural amino acid.
  • R 1 , R 2 , Xaa, Yaa, and Zaa are each selected to produce a specific MC5R peptide ligand having desired properties.
  • N-methylation of the backbone NHs as indicated in FIG.1A can provide for an increase in blood-brain barrier penetration, selectivity, and stability of the MC5R peptide ligand.
  • a non-limiting example of an MC5R peptide ligand resulting from the N-methylation of sites indicated in FIG. 1A is the following peptide, also shown in FIG. 1B, that may be used for treating CNS disorders or mood disorders:
  • R 1 is an acetyl (“Ac”)
  • R 2 is–CONH 2
  • Xaa is the natural amino acid “Asp”
  • Yaa is the natural amino acid“His”
  • Zaa is the natural amino acid“Lys”.
  • the MC5R peptide ligand is preferably a cyclic peptide formed by the bridging of Xaa to Zaa via ring closing reactions.
  • the side chain of the Xaa residue is linked to the side chain of the Zaa residue via a linker L 1 .
  • the linker L 1 is a carba, lactam, disulfide, thioether, or succinic linker.
  • the linker is not limited to the aforementioned examples, and may depend upon the specific cyclization chemistry used to produce the cyclic peptide.
  • carbon-carbon bonds, lactone, thioether, ether, disulfide and other covalent bonds can be used as a part of the ring closing reactions.
  • the type of linker can affect the structural, chemical, and biological activities of the peptide ligand.
  • the MC5R peptide ligand may be a 23-membered ring.
  • the MC5R peptide ligand is a 23-membered ring.
  • the MC5R peptide ligand may be a 23 to 29-membered ring.
  • Zaa is Orn and Xaa is Glu
  • the MC5R peptide ligand is a 23-membered ring.
  • the MC5R peptide ligand is a 24- membered ring.
  • the ring size of the MC5R peptide ligand can affect the selectivity of the peptide ligand.
  • a 23-membered ring may provide a universal peptide ligand for MC1R, MC3R, MC4R, and MC5R.
  • the peptide ligand may be selective for a particular melanocortin receptor, such as MC1R and MC5R.
  • Table 1 summarizes the modifications on the MC5R peptide ligand.
  • TABLE 2 shows non-limiting examples of the MC5R peptide ligand of the present invention, wherein Xaa is Asp, Zaa is Lys, R 1 is Ac, and R 2 is–CONH 2 .
  • Xaa is Asp
  • Zaa is Lys
  • R 1 is Ac
  • R 2 is–CONH 2 .
  • “NH 2 ” in a sequence refers to–CONH 2 .
  • R 1 can be an acetyl, a glycosylated amino acid,–CO- (CH 2 ) n CH 3 , or–CO-(CH 2 ) n CF 3 , wherein‘n’ ranges from 1 to 6, and R 2 can be–CONH 2 , –CO OH, or–CH 2 OH.
  • TABLE 4 shows non-limiting examples of the MC5R peptide ligand of the present invention.
  • Xaa is Glu
  • Zaa is Orn
  • R 1 is–CO-(CH 2 )CH 3
  • R 2 is–CONH 2 .
  • TABLE 5 shows non-limiting examples of the MC5R peptide ligand of the present invention.
  • Xaa is Glu
  • Zaa is Lys
  • R 1 is glucosylated Ser (Ser- O-Glc)
  • R 2 is–COOH.
  • “OH” in a sequence refers to–COOH.
  • a central nervous system (CNS) disorder may include, but are not limited to, stress, Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), an ascular disorder, such as stroke, transient ischemic attack (TIA), subarachnoid hemorrhage, subdural hemorrhage and hematoma, and extradural hemorrhage; an infection, such as meningitis, encephalitis, polio, and epidural abscess; a structural disorder, such as brain or spinal cord injury, Bell's palsy, cervical spondylosis, carpal tunnel syndrome, brain or spinal cord tumors, peripheral neuropathy, and Guillain-Barré syndrome; a functional disorder, such as headache, epilepsy, dizziness, and neuralgia; or degeneration, such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Huntington's chorea,
  • TS stress, Tourette
  • Symptoms of CNS disorders may include, but are not limited to, headaches, loss of feeling or tingling, muscle weakness or loss of muscle strength, sudden loss of sight or double vision, memory loss, impaired mental ability, lack of coordination, muscle rigidity, tremors and seizures, back pain, muscle wasting, slurred speech, and motor and vocal tics.
  • Stress may be defined as the brain's response to any demand, or any uncomfortable emotional experience accompanied by predictable biochemical, physiological and behavioral changes. Stress is often described as a feeling of being overwhelmed, concerned or run-down, which can lead to both physical and psychological health issues.
  • Chronic stress which is constant and persists over an extended period of time, can have health consequences and adversely affect the immune, cardiovascular, neuroendocrine and central nervous systems.
  • Chronic stress can occur in response to everyday stressors that are ignored or poorly managed, as well as to exposure to traumatic events, such as acute stress disorder (ASD) or post- traumatic stress disorder (PTSD).
  • ASD acute stress disorder
  • PTSD post- traumatic stress disorder
  • chronic stress can cause or exacerbate health problems such as anxiety, depression, high blood pressure, a weakened immune system, heart disease, digestive problems such as ulcers, weight problems such as obesity, skin conditions, such as eczema, reproductive issues, pain of any kind, sleep problems such as insomnia, cognitive and memory problems.
  • a major depressive disorder is a common disorder of mood and affect characterized by one or more major depressive episodes. These episodes are defined diagnostically using a criteria-based syndrome listed and described in literature as would be known to one of ordinary skill in the art. These episodes are diagnosed in a human patient if the patient has experienced 5 symptoms from a list of 9 symptom categories every day, or nearly every day, for a period lasting at least 2 weeks. At least one symptom must be present from either category 1 (having a sad, depressed, empty, or irritable mood, or appearing sad to others), or category 2 (experiencing loss of interest in or pleasure from activities).
  • category 1 having a sad, depressed, empty, or irritable mood, or appearing sad to others
  • category 2 experiencing loss of interest in or pleasure from activities.
  • the other symptom categories include: 3) change in weight and/or appetite, 4) insomnia or hypersomnia, 5) psychomotor agitation or retardation, 6) fatigue and/or loss of energy, 7) feelings of worthlessness and/or excessive or inappropriate guilt, 8) diminished ability to think or of concentrate and/or indecisiveness, and 9) recurrent thoughts of death or suicide.
  • Persistent depressive disorder also known as dysthymia, is a chronic (ongoing) type of depression in which a person's moods are regularly low. However, the symptoms are not as severe as with major depression.
  • Bipolar Disorder also known as“manic-depressive illness” is a mood disorder arising in a human patient who experiences major depressive episodes which alternate with episodes of mania (in the case of type I) or hypomania (in the case of type II).
  • Mania is a syndrome characterized by a euphoric, expansive, or irritable mood lasting at least one week.
  • at least three of the following symptoms persisted during the same time period: inflated self esteem and/or grandiosity, decreased need for sleep, increased volume or rate of speech, flight of ideas and/or racing thoughts, distractibility, increased goal-directed activity and/or psychomotor agitation, excessive involvement in pleasurable activities that have a high potential for painful consequences.
  • Bipolar affective disorder is characterized by two or more episodes in which the patient's mood and activity levels are significantly disturbed, this disturbance consisting on some occasions of an elevation of mood and increased energy and activity (hypomania or mania) and on others of a lowering of mood and decreased energy and activity (depression). Repeated episodes of hypomania or mania only are classified as bipolar. This includes manic depressive illness, psychosis, and reaction. This excludes bipolar disorder, single manic episode and cyclothymia.
  • Bipolar affective disorder current episode mild or moderate depression, the patient is currently depressed, as in a depressive episode of either mild or moderate severity, and has had at least one authenticated hypomanic, manic, or mixed affective episode in the past.
  • Bipolar affective disorder current episode severe depression without psychotic symptoms, the patient is currently depressed, as in severe depressive episode without psychotic symptoms, and has had at least one authenticated hypomanic, manic, or mixed affective episode in the past.
  • Treatment-resistant depression is exemplified by a case in which a human patient with either major depressive disorder or bipolar disorder continues to meet criteria for a major depressive episode in spite of treatment with conventional antidepressant drugs at adequate doses and treatment durations (at least 4 to 8 weeks).
  • Panic Disorder is an episodic paroxysmal anxiety syndrome characterized by recurrent attacks of severe anxiety (panic) which are not restricted to any particular situation or set of circumstances and are therefore unpredictable. The symptoms include sudden onset of palpitations, chest pain, dyspnea, dizziness, and feelings of unreality (depersonalization or derealization). There is often also a secondary fear of dying, losing control, or going proficient.
  • Panic disorder may be seen with or without agoraphobia, which is characterized by a cluster of phobias embracing fears of leaving home, entering shops, crowds and public places, or traveling alone in trains, buses or planes. Avoidance of the phobic situation is prominent, to an extent that agoraphobics alter their lifestyles to avoid their relevant phobic situations.
  • Social phobia also called Social Anxiety Disorder
  • Social phobia is characterized by a marked and persistent fear of one or more social or performance settings in which the patient is exposed to unfamiliar people or to possible scrutiny by other people. The patient fears that in such situation they will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing. Exposure to the feared social situation almost invariably provokes anxiety, and this response may progress to panic attacks.
  • Post-traumatic stress disorder arises as a delayed or protracted response to a stressful event or situation (of either brief or long duration) of an exceptionally threatening or catastrophic nature which is likely to cause pervasive distress in almost anyone.
  • Predisposing factors such as personality traits or previous history of mood or anxiety disorders, may lower the threshold for the development of the syndrome or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence.
  • Typical features include episodes of repeated reliving of the trauma in intrusive memories (“flashbacks”), dreams or nightmares occurring against the persisting background of a sense of “numbness” and emotional blunting, detachment from other people, unresponsiveness to surroundings, anhedonia, and avoidance of activities and situations reminiscent of the trauma.
  • flashbacks intrusive memories
  • nightmares occurring against the persisting background of a sense of “numbness” and emotional blunting, detachment from other people, unresponsiveness to surroundings, anhedonia, and avoidance of activities and situations reminiscent of the trauma.
  • Anxiety and depression commonly are associated with these symptoms and signs.
  • the onset follows the trauma with a latency period that may range from a few weeks to months.
  • Generalized anxiety disorder is a chronic anxiety syndrome characterized by excessive worry or anxiety over a period lasting at least 6 months.
  • A“subject” is an individual and includes, but is not limited to, a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent), a fish, a bird, a reptile or an amphibian.
  • a mammal e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent
  • a fish e.g., a bird, a reptile or an amphibian.
  • A“patient” is a subject afflicted with a disease or disorder.
  • the term“patient” includes human and veterinary subjects.
  • the terms“administering” and“administration” refer to methods of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, administering the compositions orally, parenterally (e.g., intravenously and subcutaneously), by intramuscular injection, by intraperitoneal injection, intrathecally, transdermally, extracorporeally, topically or the like.
  • a composition can also be administered by topical intranasal administration (intranasally) or administration by inhalant.
  • topical intranasal administration means delivery of the compositions into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism (device) or droplet mechanism (device), or through aerosolization of the composition.
  • Administration of the compositions by inhalant can be through the nose or mouth via delivery by a spraying or droplet mechanism.
  • an inhaler can be a spraying device or a droplet device for delivering a composition comprising MC5R peptide ligand, in a pharmaceutically acceptable carrier, to the nasal passages and the upper and/or lower respiratory tracts of a subject. Delivery can also be directly to any area of the respiratory system (e.g., lungs) via intratracheal intubation.
  • the exact amount of the compositions required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the severity of the disorder being treated, the particular composition used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every composition.
  • Parenteral administration of the composition is generally characterized by injection.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions.
  • a more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. See, for example, U.S. Pat. No. 3,610,795, which is incorporated by reference herein.
  • A“therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. [00117] As described above, the compositions can be administered to a subject in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • Pharmaceutical carriers are known to those skilled in the art. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically- acceptable carrier examples include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • Further carriers include sustained release preparations such as semi-permeable matrices of solid hydrophobic polymers containing the disclosed compounds, which matrices are in the form of shaped articles, e.g., films, liposomes, microparticles, or microcapsules. It will be apparent to those persons skilled in the art that certain carriers can be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. Other compounds can be administered according to standard procedures used by those skilled in the art.
  • Pharmaceutical formulations can include additional carriers, as well as thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the compounds disclosed herein. Pharmaceutical formulations can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • the pharmaceutical formulation can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topically (including ophthahnically, vaginally, rectally, intranasally), orally, by inhalation, or parenterally, for example by intravenous drip, subcutaneous, intraperitoneal or intramuscular injection.
  • the disclosed compounds can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • Preparations for parenteral administration include sterile aqueous or non- aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, fish oils, and injectable organic-esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Pharmaceutical formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • MC5R peptide ligand can be administered in an intravenous dosage. This dosage can be administered to a subject once daily or in divided dosages throughout a day, as determined by methods known in the art.
  • This dosage can be administered to a subject for one day and then stopped if the subject responds immediately, or the dosage can be administered on a daily basis until a clinical response is noted. It is contemplated that the dosage of the MC5R peptide ligand can be administered as infrequently as once every month or every two months, or at any interval in between, depending on a subject's clinical response to the medication. Thus, if a subject responds to one dosage of the MC5R peptide ligand, a person of skill may determine that further dosages of the medication can be withheld. Moreover, if a subject does not respond to the initial dosage and administration of the MC5R peptide ligand, a person of skill can administer the medication daily for several days until such response occurs.
  • a person of skill can monitor a subject's clinical response to the administration of the MC5R peptide ligand, and administer additional dosages if the subject's mood disorder symptoms reappear after a period of remission. It is contemplated that the MC5R peptide ligand, can be administered to a subject with, for example, major mood disorder on a daily basis, on an alternating daily basis, on a weekly basis, on a monthly basis, or at any interval in between. [00125] In another aspect, the MC5R peptide ligand can be administered to a subject transdermally, by using an adherent patch, by using iontophoresis, or by using any other method known to a person of skill.
  • the dosage of the MC5R peptide ligand, administered transdermally, can be given daily or infrequently as once every 1 to 4 weeks.
  • a person of skill, monitoring a subject's clinical response and improvement, can determine the frequency of administration by methods known in the art.
  • the MC5R peptide ligand can be administered to a subject intranasally in a dosage taken once daily or in divided doses.
  • the medication can be administered for one day and then stopped if clinical improvement occurs rapidly. Further, the medication can be administered as infrequently as once every 1 to 4 weeks.
  • a person of skill, monitoring a subject's clinical response to the administration of the medication can adjust the frequency of administration according to methods known in the art.
  • the MC5R peptide ligand can be administered to a subject intramuscularly in a dosage taken once daily or in divided doses. The medication can be administered for one day and then stopped if clinical improvement occurs rapidly. Furthermore, the medication can be administered as infrequently as once every 1 to 4 weeks. A person of skill, monitoring a subject's clinical response, can adjust the frequency of administration of the medication according to methods known in the art.
  • the MC5R peptide ligand can be administered to a subject orally in a dosage taken once daily or in divided doses. The medication can be administered for one day and then stopped if clinical improvement occurs rapidly. Furthermore, the medication can be administered as infrequently as once every 1 to 4 weeks. A person of skill, monitoring a subject's clinical response, can adjust the frequency of administration of the medication according to methods known in the art. [00129] EXAMPLES
  • the psychiatrist recommends a trial of the MC5R peptide ligand administered using a transdermal patch.
  • the patient is given a patch comprising the MC5R peptide ligand dose of 20 mg for transdermal delivery over a period 24 hours.
  • a patch is to be administered every day for two weeks, followed by a visit with her psychiatrist.
  • the patient retakes the EPDS test and scores a 12. She reports that her symptoms have drastically lessened in the past two weeks.
  • Her psychiatrist prescribes another treatment of a transdermal patch comprising the MC5R peptide ligand dose of 10 mg for transdermal delivery over a period 24 hours.
  • the patch is to be administered every other day for two weeks, followed by a visit with her psychiatrist.
  • the patient continues to improve and is no longer suffering from post-partum depression 6 months later. No side effects are reported.
  • the following example describes a treatment strategy for depression involving the repeated administration of the MC5R peptide ligand.
  • a 52 year old female has a strong family history of depression and has had disabling depression since her teens. She has been tried on numerous oral medications without benefit. At times she is agitated and has panic attacks, which fluctuates with lethargy and insomnia. She is referred to a neurologist, who rules out any secondary causes for her symptoms. Her brain MRI scan and routine lab testing is within normal limits. Her psychiatrist recommends a trial of the MC5R peptide ligand administered intravenously.
  • a fixed IV of the MC5R peptide ligand dose (1 mg/kg infusion over 30 minutes) is repeated administered every two days over a two to three week period in hospital.
  • a follow up visit with her psychiatrist reveals improving depression symptoms with less agitation, improved energy levels and sleep patterns.
  • a second treatment of the fixed IV of the MC5R peptide ligand is given two months later. The patient continues to improve and is functioning normally at 6 months. No side effects are reported.
  • the term“about” refers to plus or minus 10% of the referenced number.
  • descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as“consisting of”, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase“consisting of” is met.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des compositions et des procédés de traitement d'un trouble du système nerveux central (SNC) ou d'un trouble de l'humeur chez un sujet ayant besoin d'un tel traitement. Une quantité thérapeutiquement efficace d'une composition comprenant un ligand de peptide de récepteur de mélanocortine 5 (MC5R) dans un véhicule pharmaceutiquement acceptable est administrée au sujet. Le ligand de peptide MC5R est un antagoniste sélectif de MC5R, l'administration de celui-ci au sujet pouvant traiter le trouble du SNC ou le trouble de l'humeur avec une amélioration clinique observée dans un temps relativement court.
PCT/US2016/057364 2015-10-16 2016-10-17 Compositions et procédés de traitement de troubles du système nerveux central (snc) et de troubles de l'humeur Ceased WO2017066769A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/768,340 US10550157B2 (en) 2015-10-16 2016-10-17 Compositions and methods for treating central nervous system (CNS) disorders and mood disorders

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US201562242850P 2015-10-16 2015-10-16
US201562242907P 2015-10-16 2015-10-16
US201562242874P 2015-10-16 2015-10-16
US62/242,907 2015-10-16
US62/242,874 2015-10-16
US62/242,850 2015-10-16
US14/943,885 2015-11-17
US14/943,606 US20170022252A1 (en) 2014-06-10 2015-11-17 Novel modulators of melanocortin receptors
US14/943,606 2015-11-17
US14/943,936 US9814755B2 (en) 2014-06-10 2015-11-17 Methods for the treatment of depression and anxiety
US14/943,885 US9821023B2 (en) 2014-06-10 2015-11-17 Methods for the treatment of central nervous system (CNS) disorders and mood disorders
US14/943,936 2015-11-17

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US14/943,936 Continuation US9814755B2 (en) 2014-06-10 2015-11-17 Methods for the treatment of depression and anxiety
US14/943,885 Continuation US9821023B2 (en) 2014-06-10 2015-11-17 Methods for the treatment of central nervous system (CNS) disorders and mood disorders

Publications (1)

Publication Number Publication Date
WO2017066769A1 true WO2017066769A1 (fr) 2017-04-20

Family

ID=58518408

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/057364 Ceased WO2017066769A1 (fr) 2015-10-16 2016-10-17 Compositions et procédés de traitement de troubles du système nerveux central (snc) et de troubles de l'humeur

Country Status (1)

Country Link
WO (1) WO2017066769A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050037951A1 (en) * 1999-06-29 2005-02-17 Palatin Technologies, Inc. Composition and methods for treatment of sexual dysfunction
WO2005079574A1 (fr) * 2004-01-21 2005-09-01 Palatin Technologies, Inc. Composes bicycliques specifiques de la melanocortine
US20100129319A1 (en) * 2006-12-14 2010-05-27 Per Lindquist Treatment of disease or injury of the nervous system using agents that decrease the activity of the melanocortin 4 receptor
US20150037376A1 (en) * 2011-11-04 2015-02-05 Xion Pharmaceuticals Corporation Methods and compositions for oral administration of melanocortin receptor agonist compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050037951A1 (en) * 1999-06-29 2005-02-17 Palatin Technologies, Inc. Composition and methods for treatment of sexual dysfunction
WO2005079574A1 (fr) * 2004-01-21 2005-09-01 Palatin Technologies, Inc. Composes bicycliques specifiques de la melanocortine
US20100129319A1 (en) * 2006-12-14 2010-05-27 Per Lindquist Treatment of disease or injury of the nervous system using agents that decrease the activity of the melanocortin 4 receptor
US20150037376A1 (en) * 2011-11-04 2015-02-05 Xion Pharmaceuticals Corporation Methods and compositions for oral administration of melanocortin receptor agonist compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEE ET AL.: "Solution Structures and Molecular Interactions of Selective Melanocortin Receptor Antagonists", MOL. CELLS, vol. 30, no. 6, 31 December 2010 (2010-12-31), pages 551 - 556, XP055123000 *

Similar Documents

Publication Publication Date Title
US9821023B2 (en) Methods for the treatment of central nervous system (CNS) disorders and mood disorders
US9789155B2 (en) Methods of improving behavioral therapies
US20250154234A1 (en) Methods for treatment of refractory generalized myasthenia gravis
TWI643614B (zh) 低頻率格拉替雷（ｇｌａｔｉｒａｍｅｒ）醋酸鹽之治療
JP6722453B2 (ja) 抗不安薬組成物、製剤および使用方法
JP2010532761A5 (fr)
US9662371B2 (en) Treatment of autism and similar disorders
US10550157B2 (en) Compositions and methods for treating central nervous system (CNS) disorders and mood disorders
EP3804811A1 (fr) Traitement des troubles de l'humeur et de l'angoisse
US9814755B2 (en) Methods for the treatment of depression and anxiety
US20190255142A1 (en) Novel modulators of melanocortin receptors for the treatment of depression and anxiety
WO2017066769A1 (fr) Compositions et procédés de traitement de troubles du système nerveux central (snc) et de troubles de l'humeur
US10653743B2 (en) Methods for the treatment of depression and anxiety by a melanocortin 5 receptor antagonist, PG-20N
CA3172150A1 (fr) Methodes de toxine botulique injectable pour le traitement de maux de tete
US11542302B2 (en) Modulators of melanocortin receptors for the treatment of depression and anxiety
US20030064932A1 (en) Methods of treatment comprising administration of Substance P
JP4775940B2 (ja) アロディニアの治療、改善、予防剤
US20220062380A1 (en) Compositions, Methods and Uses of a Teneurin C-Terminal Associated Peptide-1 (TCAP-1) for Treating Opioid Addiction
JP2023094736A (ja) 疼痛治療薬
HK40046105B (en) Compositions, methods and uses of a teneurin c-terminal associated peptide-1 (tcap-1) for treating opioid addiction
HK40046105A (en) Compositions, methods and uses of a teneurin c-terminal associated peptide-1 (tcap-1) for treating opioid addiction
Gaudillière et al. Multiparameter flow cytometry analysis of opioid-mediated alteration of human immune signaling pathways: 9AP3-1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16856417

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16856417

Country of ref document: EP

Kind code of ref document: A1