Urotensin-II agonists and antagonists

Abstract

The present invention features a novel class of cyclic polypeptides that have U-II antagonist and agonist activity. The invention also features methods for treating physiological or psychological conditions characterized by an excess or an under expression of Urotensin-II.

1 . A polypeptide or a variant thereof, said polypeptide having the formula:  
         ( R   1 ) u - AA   1 -cyclo[ AA   2 - AA   3 - AA   4 - AA   5 - AA   6 -Cys]- AA   7 - R   2    wherein 
 AA 1  is the L isomer of an aromatic amino acid;  
 AA 2  is the L or D isomer of Cys;  
 AA 3  is an L isomer of an aromatic amino acid;  
 AA 4  is the L or D isomer of Tip;  
 AA 5  is the L or D isomer of Lys, N-Me-Lys, or Orn;  
 AA 6  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 AA 7  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 R 1  is H, lower alkyl, lower alkanoyl, or a lower acyl; a is 1 or 2; and R 2  is OH, OR 3 , N(R 3 ) 2  or NHR 3 , where R 3  is H, a lower alkyl, or arylalkyl; provided said peptide is not Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-NH 2 ; or  
   a pharmaceutically acceptable salt of said polypeptide or variant.    
     
     
         2 . The polypeptide of  claim 1 , wherein said aromatic amino acid has the formula:  
       
         
           
           
               
               
           
         
         wherein X is H or a bond, and Ar represents a moiety selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         wherein n is 0, 1, 2, or 3 and each substituent Y independently represents NO 2 , CN, Cl, Br, I, F, Me, COR 4 , COOR 4 , or OR 4 , groups where R 4  is H or C 1 -C 8  alkyl.  
       
     
     
         3 . The polypeptide of  claim 1 , wherein AA 3  is selected from the group consisting of Phe, Trp, Pal, His, β-Nal, 3-pyridyl-Ala, 4-pyridyl-Ala, 2,4-dichloro-phe, pentafluoro-Phe, p-Z-Phe, and o-Z-Phe, wherein Z is selected from the group consisting of Me, Cl, Br, F, OH, OMe, and NO 2 .  
     
     
         4 . The polypeptide of  claim 1 , wherein AA 4  is L-Trp.  
     
     
         5 . The polypeptide of  claim 1 , wherein AA 2  is D-Cys.  
     
     
         6 . The polypeptide of  claim 5 , wherein AA 3  is Phe, AA 4  is Trp, AA 5  is Lys, AA 6  is Thr, AA 7  is Val, and AA 1  is Cpa.  
     
     
         7 . The polypeptide of  claim 6 , wherein said polypeptide has the formula Cpa-c[D-Cys-Phe-Trp-Lys-Thr-Cys]-Val-NH 2  (SEQ D NO: 5).  
     
     
         8 . A pharmaceutical composition comprising a polypeptide, or a variant thereof, and a pharmaceutically acceptable carrier, said polypeptide having the formula:  
         ( R   1 ) u - AA   1 -cyclo[ AA   2 - AA   3 - AA   4 - AA   5 - AA   6 -Cys]- AA   7 - R   2    wherein 
 AA 1  is the L isomer of an aromatic amino acid;  
 AA 2  is the L or D isomer of Cys;  
 AA 3  is an L isomer of an aromatic amino acid;  
 AA 4  is the L or D isomer of Trp;  
 AA 5  is the L or D isomer of Lys, N-Me-Lys, or Orn;  
 AA 6  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 AA 7  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 R 1  is H, lower alkyl, lower alkanoyl, or a lower acyl; a is 1 or 2; and R 2  is OH, OR 3 , N(R 3 ) 2  or NHR 3 , where R 3  is H, a lower alkyl, or arylalkyl; provided said peptide is not Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-NH 2 ; or  
   a pharmaceutically acceptable salt of said polypeptide or variant.    
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said aromatic amino acid has the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is H or a bond, and Ar represents a moiety selected from the group consisting of  
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, or 3 and each substituent Y independently represents NO 2 , CN, Cl, Br, I, F, Me, COR 4 , COOR 4 , or OR 4 , groups, where R 4  is H or C 1 -C 8  alkyl.  
       
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein AA 3  is selected from the group consisting of Phe, Trp, Pal, His, β-Nal, 3-pyridyl-Ala, 4-pyridyl-Ala, 2,4-dichloro-phe, pentafluoro-Phe, p-Z-Phe, and o-Z-Phe, wherein Z is selected from the group consisting of Me, Cl, Br, F, OH, OMe, and NO 2 .  
     
     
         11 . The pharmaceutical composition of  claim 8 , wherein AA 4  is L-Trp.  
     
     
         12 . The pharmaceutical composition of  claim 8 , wherein AA 2  is D-Cys.  
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein AA 3  is Phe, AA 4  is Trp, AA 5  is Lys, AA 6  is Thr, AA 7  is Val, and AA 8  is Cpa.  
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein said polypeptide has the formula Cpa-c[D-Cys-Phe-Trp-Lys-Thr-Cys]-Val-NH 2  (SEQ ID NO: 5).  
     
     
         15 . The pharmaceutical composition of  claim 8 , wherein said carrier is selected from the group consisting of saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.  
     
     
         16 . A method of preventing or treating an abnormal condition characterized by an excess of Urotensin-II activity, said method comprising administering to a subject a therapeutically effective amount of a polypeptide, or variant thereof, said polypeptide having the formula:  
         ( R   1 ) u - AA   1 -cyclo[ AA   2 - AA   3 - AA   4 - AA   5 - AA   6 -Cys]- AA   7 -R 2    wherein 
 AA 1  is the L isomer of an aromatic amino acid;  
 AA 2  is the L or D isomer of Cys;  
 AA3 is an L isomer of an aromatic amino acid;  
 AA 4  is the L or D isomer of Trp;  
 AA 5  is the L or D isomer of Lys, N-Me-Lys, or Orn;  
 AA 6  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 AA 7  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 R 1  is H, lower alkyl, lower alkanoyl, or a lower acyl; a is 1 or 2; and R 2  is OH, OR 3 , N(R 3 ) 2  or NHR 3 , where R 3  is H, a lower alkyl, or arylalkyl; or a pharmaceutically acceptable salt thereof.  
   
     
     
         17 . The method of  claim 16 , wherein said condition is selected from the group consisting of ischaemic heart disease, congestive heart failure, portal hypertension, variceal bleeding, hypotension, angina pectoris, myocardial infarction, ulcers, anxiety, schizophrenia, manic depression, delirium, dementia, mental retardation, and dyskinesia.  
     
     
         18 . The method of  claim 17 , wherein said condition is ischaemic heart disease.  
     
     
         19 . The method of  claim 17 , wherein said condition is congestive heart failure.  
     
     
         20 . The method of  claim 17 , wherein said condition is portal hypertension  
     
     
         21 . The method of  claim 17 , wherein said condition is variceal bleeding.  
     
     
         22 . A method of modulating the effect of a Urotensin-II (U-II) peptide, said method comprising administering to a subject a polypeptide, or variant thereof, said polypeptide having the formula:  
         ( R   1 ) u - AA   1  -cyclo[ AA   2 - AA   3 - AA   4 - AA   5 - AA   6 -Cys]- AA   7 - R   2    wherein 
 AA 1  is the L isomer of an aromatic amino acid;  
 AA 2  is the L or D isomer of Cys;  
 AA 3  is an L isomer of an aromatic amino acid;  
 AA 4  is the L or D isomer of Trp;  
 AA 5  is the L or D isomer of Lys, N-Me-Lys, or Orn;  
 AA 6  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 AA 7  is the L or D isomer of Val, Thr, Leu, Ile, tert-Leu, Abu, Nle, or an aromatic amino acid;  
 R 1  is H, lower alkyl, lower alkanoyl, or a lower acyl; a is 1 or 2; and R 2  is OH, OR 3 , N(R 3 ) 2  or NHR 3 , where R 3  is H, a lower alkyl, or arylalkyl; or  
   a pharmaceutically acceptable salt thereof.    
     
     
         23 . The method of  claim 22 , wherein said modulating comprises decreasing the effect of said U-II peptide.  
     
     
         24 . A urotensin II agonist polypeptide, or variant thereof, said polypeptide having the formula: Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH (SEQ ID NO: 3).  
     
     
         25 . A method of modulating the effect of a Urotensin-II (U-II) peptide, said method comprising administering to a subject the polypeptide of  claim 24 .  
     
     
         26 . The method of  claim 25 , wherein said modulating comprises increasing the effect of said U-II peptide.  
     
     
         27 . A method of preventing or treating an abnormal condition characterized by an under expression of Urotensin-II activity, said method comprising administering to a subject a therapeutically effective amount of the polypeptide of  claim 24.