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:
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:
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。
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:
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:
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:
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.
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:
The invention is directed to a new .mu.-conotoxin named GIIIA. .mu.-Conotoxin PIIIA consists of 22 amino residues and is found in the Eastern Pacific fish-hunting species Conus purpurascens. This conotoxin is a new Na.sup.+ channel blocker and can be used to resolve tetrodotoxin-sensitive sodium channels into three categories: 1) sensitive to .mu.-PIIIA and .mu.-conotoxin GIIIA; 2) sensitive to .mu.-PIIIA but not to .mu.-GIIIA; and 3) sensitive to neither of these two .mu.-conotoxins. In rat brain, binding competition studies between the two .mu.-conotoxins and saxitoxin suggest at least three pharmacologically distinguishable binding sites. Thus, .mu.-conotoxin PIIIA should be a key tool for distinguishing among different sodium channel subtypes.
摘要:
Substantially pure conotoxin peptides are provided which inhibit synaptic transmissions at the neuromuscular junctions and which are useful both in vivo and in assays because they specifically target particular skeletal nAChRs to the exclusion of neuronal nAChRs. The peptides are of such length that they can be made by chemical synthesis, and the preferred peptides have formula: H-His-4Hyp-4Hyp-Cys-Cys-Leu-Tyr-Gly-Lys-Cys-Arg-Arg-Tyr-4Hyp-Gly-Cys-Ser-Ser-Ala-Ser-Cys-Cys-Gln-Xaa.sub.24 -NH.sub.2 wherein Xaa.sub.24 is Arg or Gly.