Mu opioid receptor agonist analogs of the endomorphins

Abstract

The invention relates to cyclic peptide agonists that bind to the mu (morphine) opioid receptor and their use in the treatment of acute and/or chronic pain. Embodiments of the invention are directed to cyclic pentapeptide and hexapeptide analogs of endomorphin that have (i) a carboxy-terminal extension with an amidated amino acid and (ii) a D-amino acid substitution in position 2. These peptide analogs exhibit decreased tolerance relative to morphine, increased solubility compared to similar tetrapeptide analogs, while maintaining favorable or improved therapeutic ratios of analgesia to side effects.

What is claimed is: 
     
         1 . A cyclic peptide of Formula I: 
       
         
           
                 
                 
               
                     
                   (I) 
                 
                     
                   H-Tyr-cyclo[X 1 -X 2 -X 3 -X 4 ]-X 5 , 
                 
             
                
                
               
            
           
         
       
       wherein
 X 1  and X 4  each independently is an acidic D-amino acid or a basic D-amino acid; 
 X 2  and X 3  each independently is an aromatic amino acid; 
 X 5  is selected from the group consisting of Ala-NHR, Arg-NHR, Asn-NHR, Asp-NHR, Cys-NHR, Glu-NHR, Gln-NHR, Gly-NHR, His-NHR, Ile-NHR, Leu-NHR, Met-NHR, Orn-NHR, Phe-NHR, Pro-NHR, Ser-NHR, Thr-NHR, Trp-NHR, Tyr-NHR, and Val-NHR, 
 
       wherein R is H or an alkyl group; and
 there is an amide bond between an amino group and a carboxylic acid group on side chains of amino acids X 1  and X 4 ; 
 with the proviso that when X 1  is an acidic amino acid, then X 4  is a basic amino acid; 
 and when X 1  is a basic amino acid, then X 4  is an acidic amino acid. 
 
     
     
         2 . The peptide of  claim 1  wherein:
 (i) X 1  is selected from the group consisting of D-Lys and D-Orn; and X 4  is selected from the group consisting of D-Asp, D-Glu, Asp, and Glu; or 
 (ii) X 1  is selected from the group consisting of D-Asp and D-Glu; and X 4  is selected from the group consisting of D-Lys, D-Orn, Lys, and Orn. 
 
     
     
         3 . The peptide of  claim 1 , wherein:
 X 2  is selected from the group consisting of Trp, Phe, and N-alkyl-Phe, wherein the alkyl group of N-alkyl-Phe comprises 1 to about 6 carbon atoms; and   X 3  is selected from the group consisting of Phe, D-Phe, and p-Y-Phe, wherein Y is NO 2 , F, Cl, or Br.   
     
     
         4 . The peptide of  claim 3 , wherein X 2  is N-methyl-Phe. 
     
     
         5 . The peptide of  claim 3 , wherein X 3  is p-Cl-Phe. 
     
     
         6 . The peptide of  claim 1 , wherein R is H. 
     
     
         7 . The peptide of  claim 1 , wherein R is H and X 5  is Gly-NH 2  or Val-NH 2 . 
     
     
         8 . The peptide of  claim 1 , wherein the alkyl group is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, or isoheptyl group. 
     
     
         9 . The peptide of  claim 1 , selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                 
                     
                   Tyr-cyclo[D-Lys-Trp-Phe-Glu]-Gly-NH 2 , 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   Tyr-cyclo[D-Glu-Phe-Phe-Lys]-Gly-NH 2   
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   Tyr-cyclo[D-Orn-Phe-p-Cl-Phe-Asp]-Val-NH 2 . 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         10 . A cyclic peptide of Formula I: 
       
         
           
                 
                 
               
                     
                   (I) 
                 
                     
                   H-Tyr-cyclo[X 1 -X 2 -X 3 -X 4 ]-X 5 , 
                 
             
                
                
               
            
           
         
       
       wherein
 (i) X 1  is selected from the group consisting of D-Lys and D-Orn; and X 4  is selected from the group consisting of D-Asp, D-Glu, Asp, and Glu; or (ii) X 1  is selected from the group consisting of D-Asp and D-Glu; and X 4  is selected from the group consisting of D-Lys, D-Orn, Lys, and Orn; 
 X 2  is selected from the group consisting of Trp, Phe, and N-alkyl-Phe, wherein the alkyl group of N-alkyl-Phe comprises 1 to about 6 carbon atoms 
 X 3  is selected from the group consisting of Phe, D-Phe, and p-Y-Phe, wherein Y is selected from the group consisting of NO 2 , F, Cl, and Br 
 X 5  is selected from the group consisting of Ala-NH 2 , Arg-NH 2 , Asn-NH 2 , Asp-NH 2 , Cys-NH 2 , Glu-NH 2 , Gln-NH 2 , Gly-NH 2 , His-NH 2 , Ile-NH 2 , Leu-NH 2 , Met-NH 2 , Orn-NH 2 , Phe-NH 2 , Pro-NH 2 , Ser-NH 2 , Thr-NH 2 , Trp-NH 2 , Tyr-NH 2 , and Val-NH 2 ; 
 and there is an amide bond between an amino group and a carboxylic acid group on side chains of amino acids X 1  and X 4 . 
 
     
     
         11 . The cyclic peptide of  claim 10 , wherein X 5  is Gly-NH 2 . 
     
     
         12 . The cyclic peptide of  claim 10 , wherein X 1  is selected from the group consisting of D-Lys and D-Orn; X 4  is selected from the group consisting of D-Asp and D-Glu; and X 5  is Gly-NH 2 . 
     
     
         13 . The cyclic peptide of  claim 10 , wherein the peptide has the amino acid sequence of SEQ ID NO: 4. 
     
     
         14 . A cyclic peptide of Formula I: 
       
         
           
                 
                 
               
                     
                   (I) 
                 
                     
                   H-Tyr-cyclo[X 1 -X 2 -X 3 -X 4 ]-X 5 , 
                 
             
                
                
               
            
           
         
       
       wherein
 X 1  is an acidic or basic D-amino acid, and X 4  is a basic or acidic amino acid; 
 X 2  is Trp; 
 X 3  is selected from the group consisting of Phe, D-Phe, and p-Y-Phe, wherein Y is selected from the group consisting of NO 2 , F, Cl, and Br; 
 X 5  is Gly-NH 2 ; 
 and there is an amide bond between an amino group and a carboxylic acid group on side chains of amino acids X 1  and X 4 ; 
 with the proviso that when X 1  is an acidic amino acid, then X 4  is a basic amino acid; 
 and when X 1  is a basic amino acid, then X 4  is an acidic amino acid. 
 
     
     
         15 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the peptide of  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the peptide of  claim 10 . 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the peptide of  claim 14 . 
     
     
         18 . A method of treating pain comprising administering to a subject an analgesic amount of the peptide of  claim 1 . 
     
     
         19 . A method of treating pain comprising administering to a subject an analgesic amount of the peptide of  claim 10 . 
     
     
         20 . A method of treating pain comprising administering to a subject an analgesic amount of the peptide of  claim 14 . 
     
     
         21 . A method for treating a drug dependence comprising administering to a subject a therapeutically effective amount of the peptide of  claim 1 . 
     
     
         22 . A method for treating a drug dependence comprising administering to a subject a therapeutically effective amount of the peptide of  claim 10 . 
     
     
         23 . A method for treating a drug dependence comprising administering to a subject a therapeutically effective amount of the peptide of  claim 14 . 
     
     
         24 . A method for treating a patient with a history of substance abuse comprising administering to a subject a therapeutically effective amount of the peptide of  claim 1 . 
     
     
         25 . A method for treating a patient with a history of substance abuse comprising administering to a subject a therapeutically effective amount of the peptide of  claim 10 . 
     
     
         26 . A method for treating a patient with a history of substance abuse comprising administering to a subject a therapeutically effective amount of the peptide of  claim 14 .