Methods of regulating cannabinoid receptor activity-related disorders and diseases

Abstract

This disclosure concerns the discovery of the use of fenoterol analogues for regulating cannabinoid (CB) receptor activity-related disorders and disease, such as dysregulated CB receptors, including treating a disorder or disease, such as a glioblastoma, hepatocellular carcinoma, liver cancer, colon cancer, and/or lung cancer, which is associated with altered cannabinoid receptor activity. In one example, the method includes administering to a subject having or at risk of developing a disorder or disease regulated by CB receptor activity an effective amount of a fenoterol analogue to reduce one or more symptoms associated with the disorder or disease regulated by CB receptor activity.

1 . A method of treating a disorder or disease regulated by cannabinoid (CB) receptor activity, comprising:
 administering to a subject having or at risk of developing a disorder or disease regulated by CB receptor activity an effective amount of a compound to reduce one or more symptoms associated with the disorder or disease regulated by CB receptor activity, wherein the compound has the formula   
       
         
           
           
               
               
           
         
         wherein R 1 -R 3  independently are hydrogen, acyl, alkoxy carbonyl, amino carbonyl (carbamoyl) or a combination thereof; 
         R 4  is H or alkyl having from 1 to 10 carbon atoms; 
         R 5  is 
       
       
         
           
           
               
               
           
         
         wherein Y 1 , Y 2  and Y 3  independently are hydrogen, —OR 6  and +NR 7 R 8 ; 
         R 6  is H or alkyl having from 1 to 10 carbon atoms; 
         R 7  and R 8  independently are hydrogen, alkyl having from 1 to 10 carbon atoms, alkoxy carbonyl, acyl or amino carbonyl and wherein the compound is optically active, thereby reducing the one or more symptoms associated with the disorder or disease in the subject regulated by CB receptor activity. 
       
     
     
         2 . The method of  claim 1 , wherein administering comprises administering a therapeutically effective amount of a compound, wherein R 4  within the compound is a methyl, ethyl, n-propyl, or isopropyl group. 
     
     
         3 . The method of  claim 2 , wherein administering comprises administering a therapeutically effective amount of a compound, wherein R 4  within the compound is a methyl group. 
     
     
         4 . The method of  claim 1 , wherein administering comprises administering a therapeutically effective amount of a compound, wherein R 6  within the compound is a methyl group. 
     
     
         5 . The method of  claim 1 , wherein administering comprises administering a therapeutically effective amount of a compound, wherein R 5  within the compound is one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein administering comprises administering a therapeutically effective amount of a compound, wherein R 1 ,R 2 , and R 3  within the compound are hydrogen. 
     
     
         7 . The method of  claim 1 , wherein administering comprises administering a therapeutically effective amount of (R,R′)-4′-methoxy-1-napthylfenoterol (MNF), (R,S′)-MNF, (R,R′)-ethylMNF, (R,R′)-napthylfenoterol (NF), (R,R′)-ethylNF, (R,S′)—NF and (R,R′)-4′-amino-1-napthylfenoterol (aminoNF), (R,R′)-4′-hydroxy-1-napthylfenoterol (hydroxyNF), or a combination thereof. 
     
     
         8 . The method of  claim 7 , wherein administering comprises administering a therapeutically effective amount of MNF, NF, or a combination thereof. 
     
     
         9 . The method of  claim 7 , wherein administering comprises administering a therapeutically effective amount of MNF. 
     
     
         10 . The method of  claim 1 , further comprising selecting a subject having or at risk of developing a disorder or disease regulated by CB receptor activity prior to administering a therapeutically effective amount of a compound. 
     
     
         11 . The method of  claim 10 , wherein selecting the subject having or at risk of developing a disorder or disease regulated by CB receptor activity comprises measuring CB receptor activity or expression (or both) in a sample obtained from the subject, wherein the presence of CB receptor activity or expression (or both) indicates that the subject has or is at risk of developing a disorder or disease regulated by CB receptor activity. 
     
     
         12 . The method of  claim 10 , wherein selecting the subject having or at risk of developing a disorder or disease regulated by CB activity comprises selecting a subject having a disorder or disease which, prior to administering a therapeutically effective amount of a compound, does not respond to a treatment targeting β2-AR activity. 
     
     
         13 . The method of  claim 1 , wherein the method is for use in treating a tumor expressing a CB-receptor. 
     
     
         14 . The method of  claim 1 , wherein the disorder or disease is selected from the group consisting of a primary brain tumor expressing a CB-receptor, an astrocytoma expressing a CB-receptor, a glioblastoma expressing a CB-receptor, a hepatocellular carcinoma expressing a CB-receptor, colon cancer, liver cancer, and lung cancer. 
     
     
         15 . The method  claim 1 , wherein inhibiting one or more signs or symptoms associated with the disease or disorder comprises inhibiting cellular growth, such as tumor or cancer cell growth (or both), tumor volume, or a combination thereof. 
     
     
         16 . The method of  claim 1 , wherein the CB receptor is GPR55. 
     
     
         17 . The method of  claim 17 , further comprising administering an additional therapeutic agent, such as prior to, concurrent with, or subsequent to administering a compound. 
     
     
         18 . The method of  claim 17 , wherein the additional therapeutic agent is a chemotherapeutic agent. 
     
     
         19 . The method of  claim 1 , wherein administering a therapeutically effective amount of a compound comprises administering a therapeutically effective amount of the compound with a pharmaceutically acceptable carrier. 
     
     
         20 . The method of  claim 1 , wherein the subject is a human.