CN101724026B - Melanocortin analogue as well as preparation method and application thereof - Google Patents
Melanocortin analogue as well as preparation method and application thereof Download PDFInfo
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- CN101724026B CN101724026B CN2009100663969A CN200910066396A CN101724026B CN 101724026 B CN101724026 B CN 101724026B CN 2009100663969 A CN2009100663969 A CN 2009100663969A CN 200910066396 A CN200910066396 A CN 200910066396A CN 101724026 B CN101724026 B CN 101724026B
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- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
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- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
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Classifications
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- A61K38/00—Medicinal preparations containing peptides
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- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A61P3/04—Anorexiants; Antiobesity agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- C07K14/68—Melanocyte-stimulating hormone [MSH]
- C07K14/685—Alpha-melanotropin
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Abstract
The invention discloses a melanocortin analogue as well as preparation method and application thereof. A polypeptide structure of the melanocortin analogue consists of a functional amino acid sequence and a load amino acid sequence, wherein the functional amino acid sequence is an annular melanocortin analogue consisting of heptamers, and the load amino acid sequence consists of a plurality of polypeptide segments in 47th-60th segments of HIV-1 (human immunodeficiency virus type 1)TAT (trans-activator of transcription) protein. The melanocortin analogue can be absorbed through mucous membranes or skin and used for treating male and female sexual dysfunctions, obesities and pigmentation deficiencies.
Description
Technical field
The present invention relates to a kind of melanocortin analogue.
Background technology
With the quickening pace of modern life, the increasing of WP, the influence of inherited genetic factors, men and women's sexual dysfunction, obesity, hypopigmentation disease all highlight day by day, have a strong impact on people's quality of life.Wherein, Obesity is one of well-known factor that causes common diseases such as arteriosclerosis, hypertension, heart trouble, mellitus, and the sexual life that men and women's sexual dysfunction and hypopigmentation disease cause is discord and is also badly influenced patient's physical and mental health and happy family life with disease such as skin carcinoma.
At present, a line medicine of treatment male sexual disorder is Pimobendanes such as Virga, but this type of medicine is invalid to female patient, and the response of part patient reported fades away.The medicine of treatment of obesity also has only a few, like sibutramine and orlistat.The medicine of treatment hypopigmentation disease is also few.PT-141 and MT-II be two kinds researching and developing at present men and women's sexual dysfunction, obesity, hypopigmentation disease are had the polypeptide drug of certain curative effect.
Because the block of biological cell membrane; Macromolecular drugs such as polypeptide are difficult to directly get in the body by cytolemma; So the polypeptide drug that uses at present adopts the administering mode of drug administration by injection mostly; And the treatment of men and women's sexual dysfunction, obesity, hypopigmentation disease is secular, if can develop and can then can exempt the inconvenient and painful of patient's long term injections administration through the polypeptide drug of mucous membrane or percutaneous drug delivery.Therefore, develop a kind of can be through the polypeptide drug that is used to treat men and women's sexual dysfunction, obesity, hypopigmentation disease of mucous membrane or percutaneous drug delivery must and the task of top priority, it has vast market prospect.
α-MSH is a kind of linear tridecanoic peptide that comes from preceding POMC (POMC).As far back as the 1950's; People just find maincenters such as dog, monkey, cat and rabbit are given can cause its heat and appetite inhibiting behind α-MSH that its mechanism of action is that MC-3, MC-4 acceptor produce sexual behaviour and appetite inhibiting adjusting effect among the novel melanocortin receptor hypotype MC-Rs through acting on; Afterwards, after people also found to give α-MSH to animals such as bullfrogs, its skin color can be deepened, and its mechanism is to produce skin pigment and regulate effect through acting on MC-1 acceptor among the novel melanocortin receptor hypotype MC-Rs.Research shows that the MC-Rs agonist has the potential using value at aspects such as treatment men and women sexual dysfunction, obesity, hypopigmentation diseases.
α-MSH is a linear tridecanoic peptide, and the C end contains amide structure, and N holds acetylize, and its primary structure is following:
Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH
2
People discovered that the minimum bioactive sequence of α-MSH was His-Phe-Arg-Trp afterwards; Round this core sequence; People design and have synthesized a series of these compounds; Comprise linear peptides and cyclic peptide, certain curative effect is arranged at aspects such as treatment men and women sexual dysfunction, obesity, hypopigmentation diseases.Wherein, PT-141, MT-II are wherein two kinds.
Because the barrier of biological cell membrane, macromole such as polypeptide can not directly get into cell, and this has brought difficulty for the treatment of numerous disease.Cell-penetrating peptide (CPP) is one type can carry the small peptide that macromolecular substance gets into cell, and it is worn the film ability and does not rely on classical endocytosis, also has the investigator to claim that this type small peptide is albumen transduction domain (PTD) or Trojan Horse peptide.
It is found that and confirm; The trans-activator TAT of human immunodeficiency virus HIV-1 can stride film and transfer in cytolemma and the nucleus; People find that also in the TAT albumen of HIV-1 is rich in the basic aminoacids fragment; Polypeptide fragment that this is positively charged and albumen conduction function are closely related, are referred to as the albumen transduction domain.Discover that further the sequence that the 49-57 residue in the TAT albumen of 86 amino-acid residues of total length is formed can be exercised the function of albumen conduction fully, and no cytotoxicity.These are found to be a kind of efficient, safe carrier of development, initiatively mediate polypeptide class macromole leap microbial film barrier wide prospect is provided.
Summary of the invention
The object of the present invention is to provide a kind of melanocortin analogue.
For realizing above-mentioned purpose, the present invention has taked following technical scheme:
A kind of melanocortin analogue, its polypeptide structure is:
Ac-Arg-Arg-Arg-Nle-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology, Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology,
Ac-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology,
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology,
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-N le-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology or
Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-Nle-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology;
Wherein, The toxic salt of no physiology is meant the salt that can keep parent compound expection physiologically active and can not produce toxic side effect outside any expectation, specifically can be hydrochloride, hydrobromate, vitriol, phosphoric acid salt, nitrate salt, acetate, oxalate, tartrate, SUMATRIPTAN SUCCINATE, malate, benzoate, two hydroxyl how hydrochlorate, alginates, mesylate, naphthalene sulfonate, sylvite, sodium salt, lithium salts, zinc salt, mantoquita, barium salt, calcium salt or trialkyl ammonium salts.
A kind of preparation method of melanocortin analogue; Be the solid-phase polypeptide synthesis method; May further comprise the steps: first complex functionality acidic amino acid sequences polypeptide resin; Hold the N end coupled respectively from C successively the amino-acid residue in the load acidic amino acid sequence behind the protection base on removing Nle then, sloughing N end protection base back acetylize or non-acetylize respectively, behind cracking and purifying, get final product again at last.
Melanocortin analogue is used for treating in preparation that male erectile dysfunction, female libido are low, the application of obesity or hypopigmentation disease.
The administering mode of melanocortin analogue is mucosa delivery or percutaneous drug delivery.
Contain at least a and pharmaceutically acceptable carrier or vehicle in the polypeptide composition with following structure in the said medicine:
Ac-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Ac-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-N le-c (Asp-His-Dphe-Arg-Trp-Lys)-OH or
Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH。
The application of melanocortin analogue in the plain MC-Rs agonist of preparation casting skin.
The proteic 47-60 residue segment of HIV-1TAT is made up of 14 amino-acid residues, and its primary structure is:
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-OH
The peptide sequence that the inventor will have the melanocortin analogue of MC-Rs agonist activity combines with the different polypeptide fragments that the different residues in the proteic 47-60 residue segment of HIV-1 TAT are formed; Design a kind of melanocortin analogue that can suck through mucous membrane or skin; This melanocortin analogue has the activity of MC-Rs agonist, can be used for the treatment of men and women's sexual dysfunction, obesity, hypopigmentation disease.
Polypeptide provided by the invention is made up of functional amino sequence and load acidic amino acid sequence two portions, is connected by peptide bond between its functional amino sequence and the load acidic amino acid sequence.
The structure of functional amino sequence is:
Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Its ring texture is connected by the Lactam cross-bridge.
This functional amino sequence is made up of one seven peptide.See that from structure its side chain connects into ring-type, fat-soluble increase more helps seeing through mucous membrane, skin, and its sequence is similar but inequality with other novel melanocortin receptor agonists.
Its load acidic amino acid sequence is made up of the different aminoacids fragment in the proteic 47-60 fragment of HIV-1 TAT.
Load acidic amino acid sequence 1 is made up of the proteic 55-57 amino acid fragment of HIV-1 TAT, contains three amino-acid residues, ethanoyl of covalent modification on its N end α amino, and its structure is:
Ac-Arg-Arg-Arg-OH
Load acidic amino acid sequence 2 is made up of the proteic 48-57 amino acid fragment of HIV-1 TAT, contains ten amino-acid residues, ethanoyl of covalent modification on its N end α amino, and its structure is:
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-OH
Load acidic amino acid sequence 3 is made up of the proteic 47-57 amino acid fragment of HIV-1 TAT, contains 11 amino-acid residues, ethanoyl of covalent modification on its N end α amino, and its structure is:
Ac-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-OH
Load acidic amino acid sequence 4 is made up of the proteic 47-57 amino acid fragment of HIV-l TAT, contains 11 amino-acid residues, and its structure is:
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-OH
Load acidic amino acid sequence 5 is made up of the proteic 48-60 amino acid fragment of HIV-1 TAT, contains 13 amino-acid residues, ethanoyl of covalent modification on its N end α amino, and its structure is:
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-OH
Load acidic amino acid sequence 6 is made up of the proteic 48-60 amino acid fragment of HIV-1 TAT, contains 13 amino-acid residues, and its structure is:
Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-OH
The functional amino sequence respectively with load acidic amino acid sequence 1,2,3,4,5,6 covalently bound composition 6 peptide species structures:
Ac-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Ac-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH、
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-N le-c (Asp-His-DPhe-Arg-Trp-Lys)-OH or
Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH。
The implication of common english abbreviation is among the present invention:
Ac is an ethanoyl
C is a cyclic peptide
Try is a tyrosine
Gly is a glycocoll
Arg is a l-arginine
Lys is a Methionin
Gln is the glutamy amino acid
Nle is a nor-leucine
Asp is an aspartic acid
His is a Histidine
Pro is a proline(Pro)
DPhe is the dexamphetamine propylhomoserin
Trp is a tryptophane
DMF is a N
DCM is a methylene dichloride
TFA is a trifluoroacetic acid
HBTU is benzotriazole-1-tetramethyl-phosphofluoric acid ester
NMM is the N-methylmorpholine
The inventor with different load acidic amino acid sequences with make an experiment after the functional amino sequence links to each other with peptide bond; Prove through experimental result: the link to each other polypeptide of back formation of decapeptide load acidic amino acid sequence and functional amino sequence penetrates different mucous membranes the most easily, comprises oral mucosa, stomach mucous membrane, nasal mucosa; The polypeptide that forms after tripeptides load acidic amino acid sequence links to each other with the functional amino sequence is transdermal the most easily.Experiment showed, that load acidic amino acid sequence portability provided by the invention functional amino sequence provided by the invention penetrates mucous membrane and capillary wall, and penetrable hemato encephalic barrier gets into pallium.Load acidic amino acid sequence provided by the invention is connected the back polypeptide that forms as medicine with functional amino sequence provided by the invention; Can be easy to absorb in low dose relatively very, orally become possibility with mucosa delivery thereby make through gastrointestinal mucosal and respiratory mucosa.This is that other polypeptide drugs are difficult to accomplish.Equally, because load acidic amino acid sequence portability functional amino sequence transdermal of the present invention, for exploitation provides possibility through the skin external administration.
For observing the penetrance of different polypeptides carrier to different mucous membranes; We are coupled at tripeptides, decapeptide, 11 peptide carriers respectively with green fluorescent protein; Be applied to oral mucosa, nasal mucosa, stomach mucous membrane and the skin of rat respectively, got blood in 15 minutes after the medication, and kill rat and get oral mucosa, nasal mucosa, stomach mucous membrane and skin sample; Observe penetration depth with histochemical method, detect the content of green fluorescent protein in the blood simultaneously.
Experiment showed, that the decapeptide carrier penetrates different mucous membranes the most easily, and the easiest transdermal of tripeptides carrier.
Different carriers is to the penetrance of different mucous membranes
Oral mucosa stomach mucous membrane nasal mucosa skin
The tripeptides carrier +++++ ++ ++
The decapeptide carrier ++ ++ ++ ++ ++ ++
11 peptide carriers +++++++++++
Experimentation on animals proves, the oral transmucosal administration, and decapeptide load acidic amino acid sequence is connected back formation with the functional amino sequence polypeptide can bring out the erection of male rat and the epigamic behavior of female rats.In 20 male rats, have 17 to have only obvious erection, and epigamic behavior is arranged.It is 30 minutes to 2 hours that the erectile response time length is arranged, average 60 minutes.Strong epigamic behavior appears in 10 8 of female rats.Obviously erecing and epigamic behavior all appears in a control group oral normal saline, 20 male rats and 10 female rats.In vivo tests proves, when giving polypeptide of the present invention, give the plain MC-3 of casting skin, MC-4 receptor-blocking agent SHU9119 simultaneously after, respectively tried rat and all occur obviously erecing and epigamic behavior.This explanation polypeptide of the present invention can activate the plain MC-3 of maincenter casting skin, MC-4 acceptor, and is acting through the plain MC-3 of maincenter casting skin, MC-4 acceptor, and its effect is similar to natural neurotransmitter.Because its action target spot is cns erection center, except that physiological action, also has psychological positive feedback effect, can be used for the treatment of psychological and organic male erectile dysfunction simultaneously.
Experimentation on animals is pointed out simultaneously, is having under the extraneous sexual stimulus condition, and polypeptide of the present invention can wake hyposexuality women's sexual desire up, and increases the vaginal wall blood flow.Hyposexuality betides 30% women approximately according to statistics, does not still have active drug at present it is treated.We find in experimentation on animals, and the excite sexual desires epigamic behavior of low female rats of polypeptide alternative of the present invention is found simultaneously; The intravaginal temperature raises; Explain that vaginal blood flow increases, these evidences show that the melanochrome nervous system not only regulates male penis erection and sexual desire, and regulate women's sexual desire; Be unique system that clearly regulates female libido known today, also become the low hope of treatment female libido.
Experimentation on animals proves, the oral transmucosal administration, and decapeptide load acidic amino acid sequence is connected back formation with the functional amino sequence polypeptide can suppress the foraging behavior of mouse, thereby alleviates the body weight of mouse.In 6 mouse, obvious weight loss is all arranged, compare average decline 5% with control group; A control group oral normal saline, each 6 mouse does not see obvious weight loss.In vivo tests proves, when giving polypeptide of the present invention, give the plain MC-3 of casting skin, MC-4 receptor-blocking agent SHU9119 simultaneously after, tried mouse and do not seen obvious weight loss.This explanation polypeptide of the present invention can activate the plain MC-3 of casting skin, MC-4 acceptor, and is acting through the plain MC-3 of casting skin, MC-4 acceptor.Work and be similar to natural neurotransmitter.
Experimentation on animals proves, oral transmucosal administration, but the generation of the polypeptide stimulation melanin that decapeptide load acidic amino acid sequence and functional amino sequence are connected to form.In being tried bullfrog, to compare with control group, the skin blackness improves many, and control group only gives saline water, does not see the skin color intensification.This explanation polypeptide of the present invention can activate the plain MC-1 acceptor of casting skin, and is to play a role through the plain MC-1 acceptor of casting skin, plays as natural neurotransmitter to promote the skin pigment nucleus formation.
Show that through a large amount of experimentation on animalies obvious ypotension is not found in long-term heavy dose of administration in test dog body, does not find tangible liver and kidney damage yet.
Embodiment
Following examples only are used to explain the present invention, but can not limit the present invention thus.
Embodiment 1
Synthesizing of functional amino sequences polypeptide resin
Step 1, accurately take by weighing in the reaction flask of 200 milliliters of Fmoc-Lys (Mmt)-Wang Resin addings of 10 grams (0.73 mmole/gram), and added 100 milliliters of DMF swelling resins 30 minutes, drain; With DMF vibration washing resin three times, each 50 milliliters, 2 minutes once again; Drain, add 50 milliliters of deprotecting regents (20% piperidines/DMF promptly contains the piperidines of 20% percent by volume in piperidines/DMF mixed solution) oscillatory reaction 30 minutes; Extract deprotection liquid out,, drain with DMF washing resin three times; Get a little triketohydrindene hydrate and detect, be positive.
Step 2, in reaction flask, add 50 milliliters of DMF successively, three times of molar weight Fmoc-Trp-OH, three times of molar weight HBTU, three times of molar weight NMM, oscillatory reaction 30 minutes is got a little resin and is done triketohydrindene hydrate and detect; Be negative, extract reaction solution out, shake washing resin three times with DMF again, each about one minute; Drain, add 50 milliliters of deprotection liquid in resin, oscillatory reaction 30 minutes is got a little resin and is done the triketohydrindene hydrate detection; Be positive, extract deprotection liquid out,, drain with DMF vibration washing resin three times.
Step 3, set by step 2 working method will protect successively amino acid Fmoc-Arg (Pbf)-OH, Fmoc-DPhe-OH, Fmoc-His (Trt)-OH, Fmoc-Asp (O-2-Phipr)-OH, Fmoc-Nle-OH be connected to the step resin on; Nle does not have deprotection steps; Constitute polypeptide resin, structure is:
Fmoc-Nle-Asp(O-2-Phipr)-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys(Mmt)-Wang Resin
Step 4, will be on the exsiccant step polypeptide resin add in the reaction flask, 400 milliliters of 1%TFA that will prepare again add in the reaction flask with DCM (being the TFA that contains 1% percent by volume in the TFA/DCM mixed solution) reaction solution, 25 degree reacted 1 hour down; After reaction finishes, with DCM washing resin three times, vibrate washing resin 4 times of DMF; Use 5%NMM/DMF (being the NMM that contains 5% percent by volume in the NMM/DMF mixed solution) washing resin three times again, drain the triketohydrindene hydrate tests positive; In reaction flask, add 50 milliliters of DMF, 3.8 gram HBTU, 1.1 milliliters of NMM successively, oscillatory reaction 1 hour is got a little resin and is done the triketohydrindene hydrate detection; Be negative, extract reaction solution out, again with DMF vibration washing resin three times; Methanol wash resin three times, drying obtains following structural polypeptide resin:
Fmoc-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
Step 5, will go up the step polypeptide resin set by step the deprotection method in 2 make the peptide resin that contains the functional amino sequence after removing the Fmoc protection base on the Nle, structure is:
Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
Embodiment 2
Synthesizing of polypeptide 1
To protect amino acid Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH to be connected successively by the operation of step 2 among the embodiment 1 all functionality aminoacid sequence polypeptide resin that makes among the embodiment 1, obtain polypeptide resin with it.Structure is:
Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step polypeptide resin and add 50 milliliters of 50% aceticanhydride/DMF (being the aceticanhydride that contains 50% percent by volume in aceticanhydride/DMF mixed solution); Oscillatory reaction was drained reaction solution after 30 minutes, made N after respectively washing three times with DMF, DCM, methyl alcohol to hold acetylizad polypeptide resin.Structure is:
Ac-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step resin with trifluoroacetic acid cracking and chromatogram purification after, freeze-drying makes polypeptide 1.Structure is:
Ac-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Embodiment 3
Synthesizing of polypeptide 2
To protect amino acid Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH to be connected successively by the operation of step 2 among the embodiment 1 all functionality aminoacid sequence polypeptide resin that makes among the embodiment 1, obtain polypeptide resin with it.Structure is:
Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step polypeptide resin and add 50 milliliters of 50% aceticanhydride/DMF (being the aceticanhydride that contains 50% percent by volume in aceticanhydride/DMF mixed solution); Oscillatory reaction was drained reaction solution after 30 minutes, made N after respectively washing three times with DMF, DCM, methyl alcohol to hold acetylizad polypeptide resin.Structure is:
Ac-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step resin with trifluoroacetic acid cracking and chromatogram purification after, freeze-drying makes polypeptide 2.Structure is:
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Embodiment 4
Synthesizing of polypeptide 3
To protect amino acid Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH, Fmoc-Tyr (But)-OH to be connected successively by the operation of step 2 among the embodiment 1 all functionality aminoacid sequence polypeptide resin that makes among the embodiment 1, obtain polypeptide resin with it.Structure is:
Tyr(But)-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step polypeptide resin and add 50 milliliters of 50% aceticanhydride/DMF (being the aceticanhydride that contains 50% percent by volume in aceticanhydride/DMF mixed solution); Oscillatory reaction was drained reaction solution after 30 minutes, made N after respectively washing three times with DMF, DCM, methyl alcohol to hold acetylizad polypeptide resin.Structure is:
Ac-Tyr(But)-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step resin with trifluoroacetic acid cracking and chromatogram purification after, freeze-drying makes polypeptide 3.Structure is:
Ac-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Embodiment 5
Synthesizing of polypeptide 4
To protect amino acid Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH, Fmoc-Tyr (But)-OH to be connected successively by the operation of step 2 among the embodiment 1 the functional amino sequences polypeptide resin that makes among the embodiment 1, obtain polypeptide resin with it.Structure is:
Tyr(But)-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pb-f)Arg(Pbf)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-Wang Resin
To go up the step resin with trifluoroacetic acid cracking and chromatogram purification after, freeze-drying makes polypeptide 4.Structure is:
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Embodiment 6
Synthesizing of polypeptide 5
To protect amino acid Fmoc-Gln (Trt)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH to be connected successively by the operation of step 2 among the embodiment 1 all functionality aminoacid sequence polypeptide resin that makes among the embodiment 1, obtain polypeptide resin with it.Structure is:
Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Pro-Pro-Gln(Trt)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-WangResin
To go up the step polypeptide resin and add 50 milliliters of 50% aceticanhydride/DMF (being the aceticanhydride that contains 50% percent by volume in aceticanhydride/DMF mixed solution); Oscillatory reaction was drained reaction solution after 30 minutes, made N after respectively washing three times with DMF, DCM, methyl alcohol to hold acetylizad polypeptide resin.Structure is:
Ac-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Pro-Pro-Gln(Trt)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Kys)-WangResin
To go up the step resin with trifluoroacetic acid cracking and chromatogram purification after, freeze-drying makes polypeptide 5.Structure is:
Ac-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Embodiment 7
Synthesizing of polypeptide 6
To protect amino acid Fmoc-Gln (Trt)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gln (Trt)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Arg (Pbf)-OH, Fmoc-Gly-OH to be connected successively by the operation of step 2 among the embodiment 1 all functionality aminoacid sequence polypeptide resin that makes among the embodiment 1, obtain polypeptide resin with it.Structure is:
Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg(Pbf)-Pro-Pro-Gln(Trt)-Nle-c(Asp-His(Trt)-DPhe-Arg(Pbf)-Trp-Lys)-WangResin
To go up the step resin with trifluoroacetic acid cracking and chromatogram purification after, freeze-drying makes polypeptide 6.Structure is:
Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-Nle-c(Asp-His-DPhe-Arg-Trp-Lys)-OH
Embodiment 8
Laboratory animal
Bull and female sd inbred rats, heavily about 225 restrain 250 grams.Single raising in cages, the SPF feeding environment, simulating nature daytime and night light, sufficient food and water give the rat grace time conforming before the experiment, all study of behaviour study that all the set time is accomplished (14-18 point).
Experimental technique and result
Oral cavity instillation polypeptide of the present invention (polypeptide 2 of embodiment 3) can bring out erection
Experiment finds that trans-oral instillation polypeptide of the present invention can bring out erection.Behind the oral cavity instillation various dose polypeptide of the present invention (25,50,100 and 200 nanograms/every gram body weight), experimentation on animals proves; The oral transmucosal administration, the functional amino sequence can be brought out rat erection with the polypeptide that load acidic amino acid sequence links to each other, when dosage is 100 nanograms/every gram body weight; In 20 rats, have 17 to have only erection, 11 have only strong erection; And epigamic behavior is arranged, it is 30 minutes to 2 hours that the erectile response time length is arranged, average 60 minutes.Control group is established in this experiment, is the saline water group, in each 20 rat, does not see obvious erection.
Polypeptide of the present invention is to work through the MC-3 of maincenter and MC-4 acceptor
SHU-9119 optionally blocks MC-3 and MC-4 acceptor, in our experiment, uses in the polypeptide of the present invention injection SHU-9119 (dosage 2 nanograms/every gram body weight); The result finds that (dosage is 12.5,25 to polypeptide of the present invention; 50 and 100 nanograms/every gram body weight) can't induce erection, in 20 rats; Only when 100 nanograms/every gram body weight, 2 examples are still observed slight erection.Explain that polypeptide of the present invention is that MC-3 and MC-4 acceptor through maincenter works.
Table oral cavity instillation polypeptide of the present invention can bring out erection
Dosage 12.5 25 50 100 0
Sum 9,/20 15,/20 18,/20 17,/20 0/20 erects
Strong erection 1,/20 5,/20 10,/20 11,/20 0/20
Annotate: dose unit is nanogram/every gram body weight in the table, 0 expression saline water contrast.
Conclusion: polypeptide of the present invention is a kind of polypeptide that can get into blood flow through mucous membrane, skin absorption, and experimentation on animals confirms that it has the function of triggering male penis erection, can be used for treating male erectile dysfunction.
Embodiment 9
Laboratory animal
Bull and female sd inbred rats, heavily about 225 restrain 250 grams.Single raising in cages, the SPF feeding environment, simulating nature daytime and night light, sufficient food and water give the rat grace time conforming before the experiment, all study of behaviour study that all the set time is accomplished (14-18 point).
Experimental technique and result
Oral cavity instillation polypeptide of the present invention (polypeptide 2 of embodiment 3) can bring out the female rats epigamic behavior
Experiment proof polypeptide of the present invention can make the change of female rats generation epigamic behavior.The experiment female rats is behind row bilateral oophorectomy after the anesthesia; Become hyposexuality type rat; Find in the experiment; Behind the oral cavity instillation polypeptide of the present invention (100 nanograms/every gram body weight), the frequency that female rats gets into the upper strata at male rat place increases to 11 times by average 3 times, and the time that gets into the upper strata first was reduced to 3 minutes by average 11 minutes.Can the excite sexual desires epigamic behavior of low female rats of oral cavity instillation polypeptide of the present invention is described.Find in the observation to the vagina temperature change that the intravaginal temperature raises, explain that vaginal blood flow increases.Contrast saline water is difficult effect
Polypeptide of the present invention is to work through the MC-3 of maincenter and MC-4 acceptor
SHU-9119 optionally blocks MC-3 and MC-4 acceptor, in our experiment, uses in the polypeptide of the present invention injection SHU-9119 (dosage 2 nanograms/every gram body weight); The result finds that (dosage is 12.5,25 to polypeptide of the present invention; 50 and 100 nanograms/every gram body weight) can't induce obvious epigamic behavior, in 10 rats; Only when 100 nanograms/every gram body weight, 2 examples are still observed slight epigamic behavior.Explain that polypeptide of the present invention is that MC-3 and MC-4 acceptor through maincenter works.
Conclusion: polypeptide of the present invention is a kind of polypeptide that can get into blood flow through mucous membrane, skin absorption, and experimentation on animals confirms that it has the female libido of raising function, and it is low to can be used for treating female libido.
Embodiment 10
Laboratory animal
Bull and female Kunming mouse about body weight 30 grams, are divided into some groups, 6 every group.Raise in cages, the SPF feeding environment, simulating nature daytime and night light, sufficient food and water give the mouse grace time to conform before the experiment.
Experimental technique and result
Oral cavity instillation polypeptide of the present invention (polypeptide 2 of embodiment 3) but depress appetite
But trans-oral instillation polypeptide depress appetite of the present invention is found in experiment.Oral cavity instillation various dose polypeptide (25 of the present invention; 50,100 and 200 nanograms/every gram body weight) after, experimentation on animals proves; The oral transmucosal administration; The functional amino sequence can suppress mouse appetite with the polypeptide that load acidic amino acid sequence links to each other, and when dosage was 100 nanograms/every gram body weight, mean body weight descended 5% than control group in 6 rats.Control group is established in this experiment, is the saline water group, in 6 mouse, does not see obvious weight loss.
Polypeptide of the present invention is to work through the MC-3 of maincenter and MC-4 acceptor
SHU-9119 optionally blocks MC-3 and MC-4 acceptor, in our experiment, uses in the polypeptide of the present invention injection SHU-9119 (dosage 2 nanograms/every gram body weight); The result finds; (dosage is 12.5,25,50 to polypeptide of the present invention; With 100 nanograms/every gram body weight) can't depress appetite, explain that polypeptide of the present invention is that MC-3 and MC-4 acceptor through maincenter works.
Table oral cavity instillation polypeptide of the present invention can suppress mouse appetite.
Mouse body weight (gram)
The 1st day the 3rd day the 5th day the 7th day the 9th day the 11st day
Control group 28.6 28.9 29.3 29.1 30 30.2
Administration group 28.7 27.9 28.2 28.6 28.7 28.6
Conclusion: polypeptide of the present invention is a kind of polypeptide that can get into blood flow through mucous membrane, skin absorption, and experimentation on animals confirms that it has the effect of depress appetite, can be used for the treatment of obesity.
Embodiment 11
Laboratory animal
Bullfrog
Bullfrog is shone a week under available light, make its colour of skin even.
Experimental technique and result
Oral cavity instillation polypeptide of the present invention (polypeptide 2 of embodiment 3) can urge to give birth to melanochrome
Experiment discovery trans-oral instillation polypeptide of the present invention can urge to give birth to melanochrome.Oral cavity instillation various dose polypeptide (25 of the present invention; 50,100 and 200 nanograms/every gram body weight) after, experimentation on animals proves; The oral transmucosal administration; The polypeptide that the functional amino sequence links to each other with load acidic amino acid sequence can urge to give birth to melanochrome, and when dosage was 100 nanograms/every gram body weight, the visible skin color of bullfrog was deepened.A control group injecting normal saline in its bullfrog, does not see that the obvious colour of skin changes.Explain that polypeptide of the present invention is acting through the MC-1 acceptor.
Conclusion: polypeptide of the present invention is a kind of polypeptide that can get into blood flow through mucous membrane, skin absorption, and experimentation on animals confirms that it has the short melanic effect of giving birth to, and can be used for the treatment of hypopigmentation and ultra-violet radiation resisting.
Embodiment 12
Preliminary large animal experiment
In experiment to the subcutaneous heavy dose of experimental dogs (200 micrograms/every kg body weight) subcutaneous injection polypeptide of the present invention (polypeptide 2 of embodiment 3).Do not see obvious fluctuation of blood pressure after the injection, the hepatic and renal function index is normal, and reaction symptom comprises that appetite reduces, and wherein vomit 2 injection backs.In medication later six months, observe no obvious long-term side-effects.
According to experimentation on animals, recommended doses is 0.1 milligram of a per kilogram of body weight, and the suggestion formulation is aqua or finish sublingual administration, also can be made into the mucous membrane inhalation.
Sequence table
< 110>open loud, high-pitched sound
< 120>a kind of melanocortin analogue
<130>
<160>6
<170>PatentIn version 3.4
<210>1
<211>10
<212>PRT
< 213>artificial sequence
<220>
<221>MOD_RES
<222>(1)..(1)
< 223>acetylize
<220>
<221>MOD_RES
<222>(4)..(4)
<223>Nle
<220>
<221>MOD_RES
<222>(5)..(10)
< 223>cyclisation
<220>
<221>MOD_RES
<222>(7)..(7)
< 223>D type
<400>1
Arg Arg Arg Xaa Asp His Phe Arg Trp Lys
1 5 10
<210>2
<211>17
<212>PRT
< 213>artificial sequence
<220>
<221>MOD_RES
<222>(1)..(1)
< 223>acetylize
<220>
<221>MOD_RES
<222>(11)..(11)
<223>Nle
<220>
<221>MOD_RES
<222>(12)..(17)
< 223>cyclisation
<220>
<221>MOD_RES
<222>(14)..(14)
< 223>D type
<400>2
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Xaa Asp His Phe Arg Trp
1 5 10 15
Lys
<210>3
<211>18
<212>PRT
< 213>artificial sequence
<220>
<221>MOD_RES
<222>(1)..(1)
< 223>acetylize
<220>
<221>MOD_RES
<222>(12)..(12)
<223>Nle
<220>
<221>MOD_RES
<222>(13)..(18)
< 223>cyclisation
<220>
<221>MOD_RES
<222>(15)..(15)
< 223>D type
<400>3
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Xaa Asp His Phe Arg
1 5 10 15
Trp Lys
<210>4
<211>18
<212>PRT
< 213>artificial sequence
<220>
<221>MISC_FEATURE
<222>(12)..(12)
<223>Nle
<220>
<221>SITE
<222>(13)..(18)
< 223>cyclisation
<220>
<221>SITE
<222>(15)..(15)
< 223>D type
<400>4
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Xaa Asp His Phe Arg
1 5 10 15
Trp Lys
<210>5
<211>20
<212>PRT
< 213>artificial sequence
<220>
<221>MOD_RES
<222>(1)..(1)
< 223>acetylize
<220>
<221>MOD_RES
<222>(14)..(14)
<223>Nle
<220>
<221>MOD_RES
<222>(15)..(20)
< 223>cyclisation
<220>
<221>MOD_RES
<222>(17)..(17)
< 223>D type
<400>5
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln Xaa Asp His
1 5 10 15
Phe Arg Trp Lys
20
<210>6
<211>20
<212>PRT
< 213>artificial sequence
<220>
<221>MISC_FEATURE
<222>(14)..(14)
<223>Nle
<220>
<221>SITE
<222>(15)..(20)
< 223>cyclisation
<220>
<221>SITE
<222>(17)..(17)
< 223>D type
<400>6
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln Xaa Asp His
1 5 10 15
Phe Arg Trp Lys
20
Claims (1)
1. melanocortin analogue is characterized in that its polypeptide structure is:
Ac-Arg-Arg-Arg-Nle-c (Asp-His-DPhe-Arg-Trp-Lys)-OH and the toxic salt of its no physiology, wherein, the toxic salt of no physiology are hydrochloride, hydrobromate, vitriol, phosphoric acid salt, nitrate salt, acetate, oxalate, tartrate, SUMATRIPTAN SUCCINATE, malate, benzoate, two hydroxyl how hydrochlorate, alginates, mesylate, naphthalene sulfonate, sylvite, sodium salt, lithium salts, zinc salt, mantoquita, barium salt, calcium salt or trialkyl ammonium salts.
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|---|---|---|---|
| CN2009100663969A CN101724026B (en) | 2009-11-06 | 2009-11-06 | Melanocortin analogue as well as preparation method and application thereof |
| PCT/CN2010/078357 WO2011054285A1 (en) | 2009-11-06 | 2010-11-03 | Melanocortin receptor agonist, preparation method and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009100663969A CN101724026B (en) | 2009-11-06 | 2009-11-06 | Melanocortin analogue as well as preparation method and application thereof |
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| CN101724026B true CN101724026B (en) | 2012-02-01 |
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| CN101724026B (en) * | 2009-11-06 | 2012-02-01 | 河南玄美生物科技有限公司 | Melanocortin analogue as well as preparation method and application thereof |
| WO2012100342A1 (en) | 2011-01-27 | 2012-08-02 | Université de Montréal | Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators |
| CN102702330B (en) * | 2012-03-01 | 2015-04-01 | 张嘎 | Intermedin analogue prepared by bonding ring core sequence with biotin or cell-penetrating peptides |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4457864A (en) * | 1981-10-23 | 1984-07-03 | University Patents, Inc. | Synthetic analogues of α-melanotropin |
| US5731408A (en) * | 1995-04-10 | 1998-03-24 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Peptides having potent antagonist and agonist bioactivities at melanocortin receptors |
| AU2004275928B2 (en) * | 2003-09-30 | 2010-03-11 | Novo Nordisk A/S | Melanocortin receptor agonists |
| CN101724026B (en) * | 2009-11-06 | 2012-02-01 | 河南玄美生物科技有限公司 | Melanocortin analogue as well as preparation method and application thereof |
-
2009
- 2009-11-06 CN CN2009100663969A patent/CN101724026B/en active Active
-
2010
- 2010-11-03 WO PCT/CN2010/078357 patent/WO2011054285A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| CN101724026A (en) | 2010-06-09 |
| WO2011054285A1 (en) | 2011-05-12 |
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