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 hydrophilic amino acid and (ii) a substitution in amino acid 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:
   H-Tyr-cyclo[X 1 —X 2 —X 3 —X 4 ]—X 5    (I),
   
       wherein
 X 1  and X 4  each independently is an acidic amino acid or a basic amino acid; 
 X 2  and X 3  each independently is an aromatic amino acid; 
 X 5  is NHR, 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, or 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, D-Orn, Lys, and 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, D-Glu, Asp, and 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 and X 5  is NH 2 . 
     
     
         7 . The peptide of  claim 1 , wherein R is H and X 5  is 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 , 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 , 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:
 Tyr-cyclo[D-Lys-Trp-Phe-Glu]-NH 2  (SEQ ID NO:1),   Tyr-cyclo[D-Glu-Phe-Phe-Lys]-NH 2  (SEQ ID NO:2),   Tyr-cyclo[D-Lys-Trp-Phe-Glu]-Gly-NH 2  (SEQ ID NO:3),   Tyr-cyclo[D-Glu-Phe-Phe-Lys]-Gly-NH 2  (SEQ ID NO:4),   Tyr-cyclo[D-Lys-Trp-Phe-Asp]-NH 2  (SEQ ID NO:5),   Tyr-cyclo[D-Glu-N-Me-Phe-Phe-Lys]-NH 2  (SEQ ID NO:6), and   Tyr-cyclo[D-Orn-Phe-p-Cl-Phe-Asp]-Val-NH 2  (SEQ ID NO:7).   
     
     
         10 . A cyclic peptide of Formula I:
   H-Tyr-cyclo[X 1 —X 2 —X 3 —X 4 1—X 5    (I),
   
       wherein
 X 1  is a basic D-amino acid and X 4  is an acidic amino acid; 
 X 2  is Trp and X 3  is an aromatic amino acid; and 
 X 5  is 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 . 
 
     
     
         11 . The peptide of  claim 10 , wherein:
 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.   
     
     
         12 . The peptide of  claim 10 , wherein:
 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.   
     
     
         13 . The peptide of  claim 10 , wherein X 3  is p-Cl-Phe. 
     
     
         14 . The peptide of  claim 10 , wherein R is H. 
     
     
         15 . The peptide of  claim 10 , wherein R is an alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, and isoheptyl group. 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the peptide of  claim 1 . 
     
     
         17 . A method of treating pain comprising administering to a subject an analgesic amount of the peptide of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the pain is selected from the group consisting of pain from a gastrointestinal disorder, chronic pain, and neuropathic pain. 
     
     
         19 . A method for treating a drug dependence comprising administering to a subject a therapeutically effective amount of the peptide of  claim 1 . 
     
     
         20 . A method of activating a mu-opioid receptor comprising contacting the mu-opioid receptor with the peptide of  claim 1 .