Cyclic tetrapeptide stereoisomers

Abstract

Cyclic tetrapeptide stereochemical isomers of CJ-15,208, pharmaceutical compositions from such cyclic tetrapeptides, and methods of using such pharmaceutical compositions. The cyclic tetrapeptide compounds and pharmaceutical compositions disclosed herein are potent analgesics active in several pain models with generally minimal tolerance and reduced likelihood to induce addiction relative to other known opiates.

What is claimed is: 
     
         1 . A method for treating and/or preventing depression and/or anxiety, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising:
 a therapeutically effective amount of a cyclic tetrapeptide comprising a structure of Formula 1 with an amino acid sequence of cyclo[Phe-Pro-Phe-Trp] (SEQ ID NO: 1), or a derivative thereof, wherein the cyclic tetrapeptide comprises an amino acid configuration selected from the group consisting of [LDLD], [LDDL], [DDLL], [DDDL], [DDLD], [LLLL], [LLDL], [DLLL], [DLDL], [LLLD], [LLDD], [DLDD], and [DLLD], and wherein amino acid configuration of the cyclic tetrapeptide does not comprise [LDLL]; and   
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable excipient or carrier. 
       
     
     
         2 . The method of  claim 1 , wherein the amino acid configuration of the cyclic tetrapeptide is selected from the group consisting of [DDLL], [DDDL], and [DDLD]. 
     
     
         3 . The method of  claim 1 , wherein the amino acid configuration of the cyclic tetrapeptide is selected from the group consisting of [DDLL] and [DDDL]. 
     
     
         4 . The method of  claim 1 , wherein the amino acid configuration of the cyclic tetrapeptide is [LDLD]. 
     
     
         5 . The method of  claim 1 , wherein the amino acid configuration of the cyclic tetrapeptide is [DDDL]. 
     
     
         6 . The method of  claim 1 , wherein the therapeutically effective amount of the cyclic tetrapeptide is effective for depression and anxiety. 
     
     
         7 . A method for treating and/or preventing depression, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising:
 a therapeutically effective amount of a cyclic tetrapeptide comprising a structure of Formula 1 with an amino acid sequence of cyclo[Phe-Pro-Phe-Trp] (SEQ ID NO: 1), or a derivative thereof, wherein the cyclic tetrapeptide comprises an amino acid configuration selected from the group consisting of [LDLD], [LDDL], [DDLL], [DDDL], [DDLD], [LLLL], [LLDL], [DLLL], [DLDL], [LLLD], [LLDD], [DLDD], and [DLLD], and wherein amino acid configuration of the cyclic tetrapeptide does not comprise [LDLL]; and   
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable excipient or carrier. 
       
     
     
         8 . The method of  claim 7 , wherein the amino acid configuration of the cyclic tetrapeptide is selected from the group consisting of [DDLL], [DDDL], and [DDLD]. 
     
     
         9 . The method of  claim 7 , wherein the amino acid configuration of the cyclic tetrapeptide is selected from the group consisting of [DDLL] and [DDDL]. 
     
     
         10 . The method of  claim 7 , wherein the amino acid configuration of the cyclic tetrapeptide is [LDLD]. 
     
     
         11 . The method of  claim 7 , wherein the amino acid configuration of the cyclic tetrapeptide is [DDDL]. 
     
     
         12 . The method of  claim 7 , wherein the therapeutically effective amount of the cyclic tetrapeptide is effective for depression. 
     
     
         13 . A method for treating and/or preventing anxiety, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising:
 a therapeutically effective amount of a cyclic tetrapeptide comprising a structure of Formula 1 with an amino acid sequence of cyclo[Phe-Pro-Phe-Trp] (SEQ ID NO: 1), or a derivative thereof, wherein the cyclic tetrapeptide comprises an amino acid configuration selected from the group consisting of [LDLD], [LDDL], [DDLL], [DDDL], [DDLD], [LLLL], [LLDL], [DLLL], [DLDL], [LLLD], [LLDD], [DLDD], and [DLLD], and wherein amino acid configuration of the cyclic tetrapeptide does not comprise [LDLL]; and   
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable excipient or carrier. 
       
     
     
         14 . The method of  claim 13 , wherein the amino acid configuration of the cyclic tetrapeptide is selected from the group consisting of [DDLL], [DDDL], and [DDLD]. 
     
     
         15 . The method of  claim 13 , wherein the amino acid configuration of the cyclic tetrapeptide is selected from the group consisting of [DDLL] and [DDDL]. 
     
     
         16 . The method of  claim 13 , wherein the amino acid configuration of the cyclic tetrapeptide is [LDLD]. 
     
     
         17 . The method of  claim 13 , wherein the amino acid configuration of the cyclic tetrapeptide is [DDDL]. 
     
     
         18 . The method of  claim 13 , wherein the therapeutically effective amount of the cyclic tetrapeptide is effective for anxiety.