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1. 发明授权

US06265541B1 Uses of &agr;-conotoxin peptides 有权
标题翻译： α-芋螺毒素肽的使用
公开(公告)号：US06265541B1
公开(公告)日：2001-07-24
申请号：US09219446
申请日：1998-12-23
申请人： Baldomero M. Olivera , J. Michael McIntosh , Doju Yoshikami , G. Edward Cartier , Siqin Luo
发明人： Baldomero M. Olivera , J. Michael McIntosh , Doju Yoshikami , G. Edward Cartier , Siqin Luo
IPC分类号： C07K1400
CPC分类号： A61K38/17 , A61K38/08 , C07K14/43504
摘要： The present invention relates to the use of &agr;-conotoxin peptides having the general formula Xaa1-Xaa2-Cys-Cys-Xaa3-Xaa4-Pro-Xaa5-Cys-Xaa6-Cys (SEQ ID NO: 1) for treating disorders regulated at neuronal nicotinic acetylcholine receptors. Such disorders include, but are not limited to, cardiovascular disorders, gastric motility disorders, urinary incontinence, nicotine addiction, mood disorders (such as bipolar disorder, unipolar depression, dysthymia and seasonal effective disorder) and small cell lung carcinoma, as well as the localization of small cell lung carcinoma. In this formula, Xaa1 is des-Xaa1, Tyr, mono-iodo-Tyr or di-iodo-Tyr, Xaa2 is any amino acid, Xaa3 is any amino acid, Xaa4 is any amino acid, Xaa5 is any amino acid and Xaa6 represents a peptide of 3-7 amino acids. Disulfide linkages exist between the first and third cysteines and the second and fourth cysteines. Pro may be replaced with hydroxy-Pro. The C-terminus may contain a hydroxyl or an amide group, preferably an amide group.
摘要翻译：本发明涉及具有用于治疗在神经元烟碱乙酰胆碱受体调节的病症的通式的α-芋螺毒素肽的用途。这些病症包括但不限于心血管疾病，胃动力障碍，尿失禁，尼古丁成瘾，情绪障碍（例如双相情感障碍，单极抑郁，精神抑郁和季节性有效障碍）和小细胞肺癌，以及小细胞肺癌的定位。在该式中，Xaa1是des-Xaa1，Tyr，单碘-Tyr或二碘-Tyr，Xaa2是任何氨基酸，Xaa3是任何氨基酸，Xaa4是任何氨基酸，Xaa5是任何氨基酸，Xaa6表示 3-7个氨基酸的肽。第一和第三半胱氨酸与第二和第四半胱氨酸之间存在二硫键。 Pro可以用羟基替代。 C末端可以含有羟基或酰胺基，优选酰胺基。

2. 发明授权

US06958323B2 Uses of α-conotoxin peptides 有权
标题翻译： α-芋螺毒素肽的使用
公开(公告)号：US06958323B2
公开(公告)日：2005-10-25
申请号：US09897465
申请日：2001-07-03
申请人： Baldomero M. Olivera , J. Michael McIntosh , Doju Yoshikami , G. Edward Cartier , Siqin Luo
发明人： Baldomero M. Olivera , J. Michael McIntosh , Doju Yoshikami , G. Edward Cartier , Siqin Luo
IPC分类号： A61K38/08 , A61K38/17 , C07K14/435 , C12N15/12 , A61K38/10 , C07K7/08
CPC分类号： A61K38/17 , A61K38/08 , C07K14/43504
摘要： The present invention relates to the use of α-conotoxin peptides having the general formula Xaa1-Xaa2-Cys-Cys-Xaa3-Xaa4-Pro-Xaa5-Cys-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Cys (SEQ ID NO:1) for treating disorders regulated at neuronal nicotinic acetylcholine receptors. Such disorders include, but are not limited to, cardiovascular disorders, gastric motility disorders, urinary incontinence, nicotine addiction, mood disorders (such as bipolar disorder, unipolar depression, dysthymia and seasonal effective disorder) and small cell lung carcinoma, as well as the localization of small cell lung carcinoma. In this formula, Xaa1 is des-Xaa1, Tyr, mono-iodo-Tyr or di-iodo-Tyr, Xaa2 is any amino acid, Xaa3 is any amino acid, Xaa4 is any amino acid, Xaa5 is any amino acid; Xaa6 is any amino acid, Xaa7 is any amino acid, Xaa8 is any amino acid, Xaa9 is des-Xaa9 or any amino acid, Xaa10 is des-Xaa10 or any amino acid, Xaa11 is des-Xaa11 or any amino acid and Xaa2 is des-Xaa12 or any amino acid. Disulfide linkages exist between the first and third cysteines and the second and fourth cysteines. Pro may be replaced with hydroxy-Pro. The C-terminus may contain a hydroxyl or an amide group, preferably an amide group.
摘要翻译：本发明涉及具有通式Xaa 1 -Xaa 2-Cys-Cys-Xaa 3 - 的α-芋螺毒素肽的用途， Xaa 4 -Pro-Xaa 5 -Cys-Xaa 6 -Xaa 7 -Xaa 8＆lt; 8＆gt; -Xaa -Xaa -Xaa 10 -Xaa 11 -Xaa 12 -Cys（SEQ ID NO： 1）用于治疗神经元烟碱乙酰胆碱受体调节的病症。这些病症包括但不限于心血管疾病，胃动力障碍，尿失禁，尼古丁成瘾，情绪障碍（例如双相情感障碍，单极抑郁，精神抑郁和季节性有效障碍）和小细胞肺癌，以及小细胞肺癌的定位。在该式中，Xaa 1是脱-Xaa 1，Tyr，单碘-Tyr或二碘-Tyr，Xaa 2是任何氨基酸Xaa 3 N是任何氨基酸，Xaa 4是任何氨基酸，Xaa 5是任何氨基酸; Xaa 6是任何氨基酸，Xaa 7是任何氨基酸，Xaa 8是任何氨基酸，Xaa 9或/ 或是任何氨基酸，Xaa 10，或者任何氨基酸，Xaa 11，或者任何氨基酸和Xaa 2是脱-Xaa 12或任何氨基酸。第一和第三半胱氨酸与第二和第四半胱氨酸之间存在二硫键。 Pro可以用羟基替代。 C末端可以含有羟基或酰胺基，优选酰胺基。

3. 发明授权

US5866682A Conopeptides AuIA, AuIB and AuIC 失效
标题翻译：多肽AuIA，AuIB和AuIC
公开(公告)号：US5866682A
公开(公告)日：1999-02-02
申请号：US857068
申请日：1997-05-15
申请人： J. Michael McIntosh , G. Edward Cartier , Doju Yoshikami , Siqin Luo , Baldomero M. Olivera
发明人： J. Michael McIntosh , G. Edward Cartier , Doju Yoshikami , Siqin Luo , Baldomero M. Olivera
IPC分类号： A61K38/00 , C07K7/08 , C07K14/435 , A61K38/04
CPC分类号： C07K14/43504 , C07K7/08 , A61K38/00 , Y10S530/857
摘要： This invention relates to relatively short peptides about 14-17 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogs to the naturally available peptides, and which include two cyclizing disulfide linkages. More specifically, the present invention is directed to conopeptides having the general formula: Gly-Cys-Cys-Ser-Tyr-Xaa.sub.1 -Xaa.sub.1 -Cys-Phe-Ala-Thr-Asn-Xaa.sub.2 -Xaa.sub.3 -Xaa.sub.4 -Cys (SEQ ID NO: 1), wherein Xaa.sub.1 is Pro or Hyp (trans-4-hydroxy-Pro), Xaa.sub.2 is Ser, Pro or Hyp, Xaa.sub.3 is Gly or Asp and Xaa.sub.4 is a Tyr or des- Xaa.sub.4. The disulfide bridges are between the first and third between the second fourth cysteine residues. The C-terminal end is preferably amidated. The invention further relates to the specific peptides AuIA: Gly-Cys-Cys-Ser-Tyr-Pro-Pro-Cys-Phe-Ala-Thr-Asn-Ser-Asp-Tyr-Cys (SEQ ID NO:2); AuIB: Gly-Cys-Cys-Ser-Tyr-Pro-Pro-Cys-Phe-Ala-Thr-Asn-Pro-Asp-Cys (SEQ ID NO:3); and AuIC: Gly-Cys-Cys-Ser-Tyr-Pro-Pro-Cys-Phe-Ala-Thr-Asn-Ser-Gly-Tyr-Cys (SEQ ID NO:4). The invention also includes pharmaceutically acceptable salts of the conopeptides.
摘要翻译：本发明涉及长度约14-17个残基的相当短的肽，其在锥形蜗牛的毒液中或天然存在的肽类似物天然可以微量天然存在，并且包括两个环化二硫键。更具体地，本发明涉及具有以下通式的肽：Gly-Cys-Cys-Ser-Tyr-Xaa1-Xaa1-Cys-Phe-Ala-Thr-Asn-Xaa2-Xaa3-Xaa4-Cys（SEQ ID NO ：1），其中Xaa1是Pro或Hyp（反式-4-羟基-Pro），Xaa2是Ser，Pro或Hyp，Xaa3是Gly或Asp，Xaa4是Tyr或des-Xaa4。二硫键位于第二个第四个半胱氨酸残基之间的第一个和第三个之间。 C末端优选酰胺化。本发明还涉及特异性肽AuIA：Gly-Cys-Cys-Ser-Tyr-Pro-Pro-Cys-Phe-Ala-Thr-Asn-Ser-Asp-Tyr-Cys（SEQ ID NO：2）。 AuIB：Gly-Cys-Cys-Ser-Tyr-Pro-Pro-Cys-Phe-Ala-Thr-Asn-Pro-Asp-Cys（SEQ ID NO：3）; 和AuIC：Gly-Cys-Cys-Ser-Tyr-Pro-Pro-Cys-Phe-Ala-Thr-Asn-Ser-Gly-Tyr-Cys（SEQ ID NO：4）。本发明还包括肽的药学上可接受的盐。

4. 发明授权

US5929034A Use of .alpha.-conotoxin MII to treat disorders resulting from nicotine-stimulated dopamine release 失效
标题翻译：使用α-毒素MII来治疗由尼古丁刺激的多巴胺释放引起的疾病
公开(公告)号：US5929034A
公开(公告)日：1999-07-27
申请号：US45926
申请日：1998-03-23
申请人： J. Michael McIntosh , Jennifer M. Kulak , Doju Yoshikami , Baldomero M. Olivera
发明人： J. Michael McIntosh , Jennifer M. Kulak , Doju Yoshikami , Baldomero M. Olivera
IPC分类号： A61K38/17 , A61K38/00
CPC分类号： A61K38/1767 , Y10S514/813
摘要： Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to mediate nicotine addiction. In addition, stimulation of nAChRs modulates release of neurotransmitters including dopamine, norepinephrine and serotonin. Thus, pharmacological manipulation of nicotinic receptors has implications for a wide variety of disorders including psychotic, mood, movement and cognitive. For most nAChRs, there are no subtype selective ligands. However, .alpha.-conotoxin MII, a small peptide from the carnivorous marine snail Conus magus, was recently isolated. This peptide has been shown to be a specific antagonist for .alpha.3.beta.2 nicotinic receptors. The peptide potently blocks part, but not all, of nicotine-stimulated dopamine release from rat brain striatal synaptosomes. In contrast it has no effect on potassium stimulated dopamine release. Other .alpha.-conotoxins specifically target distinct neuronal nAChR subtypes. .alpha.-Conotoxins thus represent new lead compounds for CNS disorders.
摘要翻译：神经元烟碱乙酰胆碱受体（nAChRs）被认为是介导尼古丁成瘾。此外，nAChRs的刺激调节神经递质的释放，包括多巴胺，去甲肾上腺素和5-羟色胺。因此，烟碱受体的药理学操作对各种各样的疾病，包括精神病，情绪，运动和认知有影响。对于大多数nAChR，没有亚型选择性配体。然而，α-毒素MII，一种来自肉食海洋蜗牛Conus magus的小肽，最近被隔离。已经显示该肽是α3β2烟碱受体的特异性拮抗剂。该肽有力地阻止了大鼠脑纹状体突触体中尼古丁刺激的多巴胺释放的部分，但并非全部。相反，它对钾刺激的多巴胺释放没有影响。其他α-酮毒素特异性靶向不同的神经元nAChR亚型。因此，α-核酸毒素代表CNS疾病的新型铅化合物。

5. 发明授权

US5780433A Use of .alpha.-conotoxin MII to treat disorders resulting from nicotine stimulated dopamine release 失效
标题翻译：使用α-毒素MII治疗由尼古丁刺激的多巴胺释放引起的疾病
公开(公告)号：US5780433A
公开(公告)日：1998-07-14
申请号：US761674
申请日：1996-12-06
申请人： J. Michael McIntosh , Jennifer M. Kulak , Doju Yoshikami , Baldomero M. Olivera
发明人： J. Michael McIntosh , Jennifer M. Kulak , Doju Yoshikami , Baldomero M. Olivera
IPC分类号： A61K38/17 , A61K38/00
CPC分类号： A61K38/1767 , Y10S514/813
摘要： Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to mediate nicotine addiction. In addition, stimulation of nAChRs modulates release of neurotransmitters including dopamine, norepinephrine and serotonin. Thus, pharmacological manipulation of nicotinic receptors has implications for a wide variety of disorders including psychotic, mood, movement and cognitive. For most nAChRs, there are no subtype selective ligands. However, .alpha.-conotoxin MII, a small peptide from the carnivorous marine snail Conus magus, was recently isolated. This peptide has been shown to be a specific antagonist for .alpha.3.beta.2 nicotinic receptors. The peptide potently blocks part, but not all, of nicotine-stimulated dopamine release from rat brain striatal synaptosomes. In contrast it has no effect on potassium stimulated dopamine release. Other .alpha.-conotoxins specifically target distinct neuronal nAChR subtypes. .alpha.-Conotoxins thus represent new lead compounds for CNS disorders.
摘要翻译：神经元烟碱乙酰胆碱受体（nAChRs）被认为是介导尼古丁成瘾。此外，nAChRs的刺激调节神经递质的释放，包括多巴胺，去甲肾上腺素和5-羟色胺。因此，烟碱受体的药理学操作对各种各样的疾病，包括精神病，情绪，运动和认知有影响。对于大多数nAChR，没有亚型选择性配体。然而，α-毒素MII，一种来自肉食海洋蜗牛Conus magus的小肽，最近被隔离。已经显示该肽是α3β2烟碱受体的特异性拮抗剂。该肽有力地阻止了大鼠脑纹状体突触体中尼古丁刺激的多巴胺释放的部分，但并非全部。相反，它对钾刺激的多巴胺释放没有影响。其他α-酮毒素特异性靶向不同的神经元nAChR亚型。因此，α-核酸毒素代表CNS疾病的新型铅化合物。

6. 发明授权

US5922679A Use of .alpha.-conotoxin MII to treat disorders resulting from nicotine-stimulated dopamine release 失效
公开(公告)号：US5922679A
公开(公告)日：1999-07-13
申请号：US45925
申请日：1998-03-23
申请人： J. Michael McIntosh , Jennifer M. Kulak , Doju Yoshikami , Baldomero M. Olivera
发明人： J. Michael McIntosh , Jennifer M. Kulak , Doju Yoshikami , Baldomero M. Olivera
IPC分类号： A61K38/17 , A61K38/00
CPC分类号： A61K38/1767 , Y10S514/813
摘要： Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to mediate nicotine addiction. In addition, stimulation of nAChRs modulates release of neurotransmitters including dopamine, norepinephrine and serotonin. Thus, pharmacological manipulation of nicotinic receptors has implications for a wide variety of disorders including psychotic, mood, movement and cognitive. For most nAChRs, there are no subtype selective ligands. However, .alpha.-conotoxin MII, a small peptide from the carnivorous marine snail Conus magus, was recently isolated. This peptide has been shown to be a specific antagonist for .alpha.3.beta.2 nicotinic receptors. The peptide potently blocks part, but not all, of nicotine-stimulated dopamine release from rat brain striatal synaptosomes. In contrast it has no effect on potassium stimulated dopamine release. Other .alpha.-conotoxins specifically target distinct neuronal nAChR subtypes. .alpha.-Conotoxins thus represent new lead compounds for CNS disorders.

7. 发明授权

US06727226B2 Mu-conopeptides 有权
公开(公告)号：US06727226B2
公开(公告)日：2004-04-27
申请号：US09910009
申请日：2001-07-23
申请人： Baldomero M. Olivera , J. Michael McIntosh , James E. Garrett , Lourdes J. Cruz , Robert M. Jones , G. Edward Cartier , John D. Wagstaff
发明人： Baldomero M. Olivera , J. Michael McIntosh , James E. Garrett , Lourdes J. Cruz , Robert M. Jones , G. Edward Cartier , John D. Wagstaff
IPC分类号： C07K708
CPC分类号： C07K14/43504 , A61K38/00
摘要： The present invention is to &mgr;-conopeptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels. Thus, the &mgr;-conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents. The &mgr;-conopeptides are also useful for treating neuromuscular disorders. The invention is further directed to nucleic acid sequences encoding the &mgr;-conopeptides and encoding propeptides, as well as the propeptides.

8. 发明授权

US06762165B2 O-superfamily conotoxin peptides 有权
标题翻译： O超家族荚果毒素肽
公开(公告)号：US06762165B2
公开(公告)日：2004-07-13
申请号：US09749637
申请日：2000-12-28
申请人： Baldomero M. Olivera , G. Edward Cartier , Maren Watkins , David R. Hillyard , J. Michael McIntosh , Richard T. Layer , Robert M. Jones
发明人： Baldomero M. Olivera , G. Edward Cartier , Maren Watkins , David R. Hillyard , J. Michael McIntosh , Richard T. Layer , Robert M. Jones
IPC分类号： C07K14435
CPC分类号： C07K14/43504 , A61K38/00
摘要： The invention relates to relatively short peptides (termed O-Superfamily conotoxins herein), about 20-40 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.
摘要翻译：本发明涉及相对较短的肽（本文中称为O超家族芋螺毒素），长度约20-40个残基，其在锥形蜗牛的毒液中天然可以微量天然存在或类似于天然可得的肽，并且其优选包括两个二硫键。

9. 发明授权

US08487075B2 Alpha-conotoxin peptides 失效
标题翻译： α-芋螺毒素肽
公开(公告)号：US08487075B2
公开(公告)日：2013-07-16
申请号：US13367839
申请日：2012-02-07
申请人： Maren Watkins , Baldomero M. Olivera , David R. Hillyard , J. Michael McIntosh , Robert M. Jones
发明人： Maren Watkins , Baldomero M. Olivera , David R. Hillyard , J. Michael McIntosh , Robert M. Jones
IPC分类号： C07K7/08 , C07K9/00
CPC分类号： C07K14/43504 , A61K38/00 , C07K7/08 , C07K9/00 , Y10S530/855 , Y10S530/857
摘要： The invention relates to relatively short peptides (termed α-conotoxins herein), about 10-30 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.
摘要翻译：本发明涉及相对短的肽（本文中称为α-芋螺毒素），长度约10-30个残基，其在锥形蜗牛的毒液中天然可以微量天然存在或类似于天然可得的肽，并且其优选包括两个二硫键。

10. 发明授权

US06277825B1 Use of conantokins for treating pain 失效
标题翻译：使用柯南金治疗疼痛
公开(公告)号：US06277825B1
公开(公告)日：2001-08-21
申请号：US09357141
申请日：1999-07-20
申请人： Baldomero M. Olivera , J. Michael McIntosh , R. Tyler McCabe , Richard T. Layer , Li-Ming Zhou
发明人： Baldomero M. Olivera , J. Michael McIntosh , R. Tyler McCabe , Richard T. Layer , Li-Ming Zhou
IPC分类号： A61K3800
CPC分类号： C07K14/43504 , A61K38/00
摘要： The present invention is directed to the use of conantokin peptides, conantokin peptide derivatives and conantokin peptide chimeras, referred to collectively as conantokins, having 10-30 amino acids, including preferably two or more &ggr;-carboxyglutamic acid residues, for the treatment of neurologic and psychiatric disorders, such as pain, e.g., as an analgesic agent.
摘要翻译：本发明涉及使用具有10-30个氨基酸，包括优选两个或更多个γ-羧基谷氨酸残基的共同称为聚对二聚腺嘌呤肽，柯南多肽衍生物和柯南多肽嵌合体用于治疗神经病学和精神疾病如疼痛，例如止痛剂。

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