CN108101978A - C-末端芳香酯化修饰的内***肽-1类似物及其合成方法和应用 - Google Patents
C-末端芳香酯化修饰的内***肽-1类似物及其合成方法和应用 Download PDFInfo
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- CN108101978A CN108101978A CN201711366704.0A CN201711366704A CN108101978A CN 108101978 A CN108101978 A CN 108101978A CN 201711366704 A CN201711366704 A CN 201711366704A CN 108101978 A CN108101978 A CN 108101978A
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- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
多肽 | Ki(μ)[nM] | Ki(δ)[nM] | Ki(δ)/Ki(μ) |
内***肽-1 | 4.55±0.16 | 5093±660 | 1119 |
类似物1 | 8.2±1.1 | >10000 | >1220 |
类似物2 | 2.46±0.81 | >10000 | >4065 |
类似物3 | 21.3±4.17 | >10000 | >469 |
Claims (10)
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Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1227829A2 (en) * | 1999-10-28 | 2002-08-07 | New England Medical Center Hospital | Novel chimeric analgesic peptides |
CN1754890A (zh) * | 2004-09-30 | 2006-04-05 | 兰州大学 | C末端修饰的内***肽1,内***肽2 |
CN101134774A (zh) * | 2006-08-31 | 2008-03-05 | 兰州大学 | 组合化学修饰的内***肽-1及其制备方法 |
EP2007790A1 (en) * | 2006-03-31 | 2008-12-31 | The University Of Queensland | Compounds and methods for the treatment of pain |
CN101928741A (zh) * | 2010-07-23 | 2010-12-29 | 南京工业大学 | 一种在有机介质体系中化学酶法制备内***肽-1的生产方法 |
CN102234315A (zh) * | 2010-04-28 | 2011-11-09 | 兰州大学 | 一种修饰内***肽-1化合物及其在镇痛方面的应用 |
CN102241737A (zh) * | 2011-04-06 | 2011-11-16 | 兰州大学 | 内***肽-1类似物及其合成和在制备镇痛药物中的应用 |
CN102659920A (zh) * | 2012-05-14 | 2012-09-12 | 兰州大学 | C端苯丙氨酸对位氨基化修饰的内***肽-1类似物及其制备和应用 |
CN103214552A (zh) * | 2012-10-31 | 2013-07-24 | 兰州大学 | 多位点修饰的内***肽-1类似物的合成和应用 |
CN104650182A (zh) * | 2015-02-05 | 2015-05-27 | 哈尔滨工业大学 | 偶联寡聚精氨酸及2位取代的内***肽-1类似物及其合成方法和应用 |
CN105131084A (zh) * | 2015-09-25 | 2015-12-09 | 兰州大学 | 基于内***肽2或Biphalin的棕榈酰化修饰的阿片肽类似物及其合成和应用 |
CN106967151A (zh) * | 2017-02-07 | 2017-07-21 | 兰州大学 | 多位点组合修饰的内***肽类似物及其合成和应用 |
-
2017
- 2017-12-18 CN CN201711366704.0A patent/CN108101978B/zh active Active
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1227829A2 (en) * | 1999-10-28 | 2002-08-07 | New England Medical Center Hospital | Novel chimeric analgesic peptides |
CN1754890A (zh) * | 2004-09-30 | 2006-04-05 | 兰州大学 | C末端修饰的内***肽1,内***肽2 |
EP2007790A1 (en) * | 2006-03-31 | 2008-12-31 | The University Of Queensland | Compounds and methods for the treatment of pain |
CN101134774A (zh) * | 2006-08-31 | 2008-03-05 | 兰州大学 | 组合化学修饰的内***肽-1及其制备方法 |
CN102234315A (zh) * | 2010-04-28 | 2011-11-09 | 兰州大学 | 一种修饰内***肽-1化合物及其在镇痛方面的应用 |
CN101928741A (zh) * | 2010-07-23 | 2010-12-29 | 南京工业大学 | 一种在有机介质体系中化学酶法制备内***肽-1的生产方法 |
CN102241737A (zh) * | 2011-04-06 | 2011-11-16 | 兰州大学 | 内***肽-1类似物及其合成和在制备镇痛药物中的应用 |
CN102659920A (zh) * | 2012-05-14 | 2012-09-12 | 兰州大学 | C端苯丙氨酸对位氨基化修饰的内***肽-1类似物及其制备和应用 |
CN103214552A (zh) * | 2012-10-31 | 2013-07-24 | 兰州大学 | 多位点修饰的内***肽-1类似物的合成和应用 |
CN104650182A (zh) * | 2015-02-05 | 2015-05-27 | 哈尔滨工业大学 | 偶联寡聚精氨酸及2位取代的内***肽-1类似物及其合成方法和应用 |
CN105131084A (zh) * | 2015-09-25 | 2015-12-09 | 兰州大学 | 基于内***肽2或Biphalin的棕榈酰化修饰的阿片肽类似物及其合成和应用 |
CN106967151A (zh) * | 2017-02-07 | 2017-07-21 | 兰州大学 | 多位点组合修饰的内***肽类似物及其合成和应用 |
Non-Patent Citations (4)
Title |
---|
JAMES E.ZADINA等: "Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine", 《NEUROPHARMACOLOGY》 * |
PEGAH VARAMINI等: "Endomorphin Derivatives with Improved Pharmacological Properties", 《CURRENT MEDICINAL CHEMISTRY》 * |
刘红美: "内***肽-1衍生多肽的设计合成、生物学活性及血脑屏障通透性研究", 《中国博士学位论文全文数据库(电子期刊)医药卫生科技辑》 * |
王长林: "C-末端修饰的内***肽-1和-2类似物设计合成、构效关系及阿片活性研究", 《中国博士论文全文数据库(电子期刊)医药卫生科技辑》 * |
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