Uses of alpha-conotoxin peptides

Abstract

The present invention relates to the use of α-conotoxin peptides having the general formula Xaa 1 -Xaa 2 -Cys-Cys-Xaa 3 -Xaa 4 -Pro-Xaa 5 -Cys-Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Xaa 11 -Xaa 12 -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, Xaa 1 is des-Xaa 1 , Tyr, mono-iodo-Tyr or di-iodo-Tyr, Xaa 2 is any amino acid, Xaa 3 is any amino acid, Xaa 4 is any amino acid, Xaa 5 is any amino acid; Xaa 6 is any amino acid, Xaa 7 is any amino acid, Xaa 8 is any amino acid, Xaa 9 is des-Xaa 9 or any amino acid, Xaa 10 is des-Xaa 10 or any amino acid, Xaa 11 is des-Xaa 11 or any amino acid and Xaa 12 is des-Xaa 12 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.

What is claimed is:  
     
         1 . A method for treating disorders regulated at neuronal nicotinic acetylcholine receptors (nAChRs) which comprises administering to a patient in need of such treatment a therapeutically effective amount of an α-conotoxin peptide having the general formula 
 Xaa 1 -Xaa 2 -Cys-Cys-Xaa 3 -Xaa 4 -Pro-Xaa 5 -Cys-Xaa 6 -Xaa 7 -Xaa8-Xaa 9 -Xaa 10  -Xaa 11 -Xaa 12 -Cys (SEQ ID NO:1)  
 wherein Xaa 1  is des-Xaa 1 , Tyr, mono-iodo-Tyr or di-iodo-Tyr, Xaa 2  is any amino acid, Xaa 3  is any amino acid, Xaa 4  is any amino acid, Xaa 5  is any amino acid; Xaa 6  is any amino acid, Xaa 7  is any amino acid, Xaa 8  is any amino acid, Xaa 9  is des-Xaa 9  or any amino acid, Xaa 10  is des-Xaa 10  or any amino acid, Xaa 11  is des-Xaa 11  or any amino acid and Xaa 12  is des-Xaa 12  or any amino acid or a pharmaceutically acceptable salt thereof, with the proviso that when the disorder is small cell lung carcinoma, then the α-conotoxin peptide is not a peptide having an amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:13.  
 
     
     
         2 . The method of  claim 1 , wherein Xaa 1  is Tyr, mono-iodo-Tyr or di-iodo-Tyr.  
     
     
         3 . The method of  claim 1 , wherein said disorder is a cardiovascular disorder.  
     
     
         4 . The method of  claim 1 , wherein said disorder is a gastric motility disorder.  
     
     
         5 . The method of  claim 1 , wherein said disorder is urinary incontinence.  
     
     
         6 . The method of  claim 1 , wherein said disorder is nicotine addiction.  
     
     
         7 . The method of  claim 1 , wherein said disorder is a mood disorder.  
     
     
         8 . The method of  claim 1 , wherein said disorder is small cell lung carcinoma.  
     
     
         9 . The method of  claim 1 , wherein said nAChR is an α3β2-containing nAChR.  
     
     
         10 . The method of  claim 1 , wherein said nAChR is an α3β4-containing nAChR.  
     
     
         11 . The method of  claim 1 , wherein said nAChR is an α7-containing nAChR.  
     
     
         12 . The method of  claim 1 , wherein said α-conotoxin peptide is selected from the group consisting of:  
       Gly-Cys-Cys-Ser-Leu-Pro-Pro-Cys-Ala-Ala-Ser-Asn-Pro-Asp-Tyr-Cys (SEQ ID NO:11);  
       Tyr-Gly-Cys-Cys-Ser-Asn-Pro-Val-Cys-His-Leu-Glu-His-Ser-Asn-Leu-Cys (SEQ ID NO:3); and  
       Gly-Cys-Cys-Ser-Asn-Pro-Val-Cys-Phe-Ala-Thr-His-Ser-Asn-Leu-Cys (SEQ ID NO:4).  
     
     
         13 . The method of  claim 12 , wherein at least one of the Pro residues is replaced with hydroxyproline.  
     
     
         14 . The method of  claim 12 , wherein a Tyr residue is incorporated on the N-terminus.  
     
     
         15 . The method of  claim 14 , wherein the Tyr residue is substituted with one or two iodines.  
     
     
         16 . The method of  claim 1 , wherein said α-conotoxin peptide has the formula Xaa-peptide, wherein Xaa is Tyr, mono-iodo-Tyr or di-iodo-Tyr and peptide is selected from the group consisting of (a) a peptide having the amino acid sequence set forth in SEQ ID NO:5, (b) a peptide having the amino acid sequence set forth in SEQ ID NO:7, (c) a peptide having the amino acid sequence set forth in SEQ ID NO:8, (d) a peptide having the amino acid sequence set forth in SEQ ID NO:9, (e) a peptide having the amino acid sequence set forth in SEQ ID NO:12 and (f) a peptide having the amino acid sequence set forth in SEQ ID NO:13.  
     
     
         17 . The method of  claim 16 , wherein at least one of the Pro residues in the peptide is replaced with hydroxyproline.  
     
     
         18 . The method of  claim 16 , wherein a Trp residue in the peptide is replaced with bromotryptophan.