Methods and compositions for treating pain

Abstract

The disclosure provides a new use of adenosine analogs for the treatment of pain through activation of neurokinin 1 (NK1) receptor signaling pathway, thereby inducing the activation of M-type potassium channel to induce outward currents. A method and pharmaceutical composition for treating pain comprising an adenonsine analog that activates NK1 receptor signaling, thereby inducing outward current are also provided.

1 . A method of treating pain, comprising administering to a subject in need thereof a therapeutically effective amount of an adenosine analog that activates NK1 receptor signaling, thereby inducing outward current. 
     
     
         2 . The method of  claim 1 , wherein the pain is acid-induced pain. 
     
     
         3 . The method of  claim 2 , wherein the pain is acid-induced muscle pain. 
     
     
         4 . The method of  claim 3 , wherein the pain is acid-induced chronic muscle pain. 
     
     
         5 . The method of  claim 1 , wherein the pain is selected from the group consisting of inflammatory pain, cancer pain, chest pain, back pain, facial pain, joint pain, muscular pain syndromes, neuropathic pain, peripheral pain, cancer and tumor pain, sympathetic pain, postoperative pain, and post-traumatic pain. 
     
     
         6 . The method of  claim 1 , wherein the pain is fibromyalgia, myofascial pain, bladder pain syndrome or pain casued by irritable bowel syndrome. 
     
     
         7 . The method of  claim 1 , wherein the adenosine analog is isolated from a  Gastrodia  extract. 
     
     
         8 . The method of  claim 1 , wherein the adenosine analog is a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 X is O, S or CH 2 ; 
 R 1  is selected from the group consisting of NHR 4 , NH(CH 2 ) n R 4 , NH—NHR 4 , NHCONHR 4 , NH—OR 4 , O—NHR 4 , and SR 4 ; 
 
         R 2  is selected from the group consisting of hydrogen (H), halogen, cyano, OR 4 , NHR 4 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl (Ar), substituted or unsubstituted aralkyl, and a substituted or unsubstituted heterocyclyl; 
         R 3  is selected from the group consisting of halomethyl, hydroxymethyl (HOCH 2 ), alkoxymethyl (R 4 OCH 2 ), azidomethyl (N 3 CH 2 ), aminomethyl (H 2 NCH 2 ), substituted or unsubstituted aminomethyl, amidomethyl (H 2 NCOCH 2 ), sulfanylmethyl (R 4 S), sulfonylmethyl (R 4 SO 2 ), triazolylmethyl, cyanomethyl (N≡CCH 2 ), cyano, substituted or unsubstituted carbonyl (R 4 CO), COOH, COOR 4 , substituted or unsubstituted aminocarbonyl (R 4 HNCO), substituted or unsubstituted alkynyl, and substituted or unsubstituted tetrazole; 
         n is 1,2 or 3; 
         each instance of R 4  is independently selected from the group consisting of H, substituted or unsubstituted alkyl, cycloalkyl, substituted or unsubstituted Ar, substituted or unsubstituted aralkyl, and a substituted or unsubstituted heterocyclyl; 
         Ar is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted polyarene, and a substituted or unsubstituted heterocycle. 
       
     
     
         9 . The method of  claim 8 , wherein the adenosine analog is a compound of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The method of  claim 9 , wherein the adenosine analog is N 6 -(4-hydroxybenzyl)adenosine having the formula T1-11: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 9 , wherein the adenosine analog is N 6 -(4-hydroxybenzyl)adenosine having the formula JMF 1998: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method of  claim 9 , wherein the adenosine analog is a compound having the formula JMF2665: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The method of  claim 8 , wherein the adenosine analog is a compound of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein Het is an optionally substituted heterocycle of 5- or 6-membered ring or fused ring containing at least one nitrogen, oxygen or sulfur heteroatoms. 
       
     
     
         14 . The method of  claim 13 , wherein Het is selected from the group consisting of pyrrole, furan, thiophene, pyridine, piperidine, piperazine, indole, benzofuran, benzothiophene, and quinoline. 
     
     
         15 . The method of  claim 14 , wherein the adenosine analog is a compound having the formula JMF 1907: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The method of  claim 8 , wherein the adenosine analog is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The method of  claim 16 , wherein the adenosine analog is a compound having the formula CGS21680: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
       
     
     
         18 . The method of  claim 1 , wherein the adenosine analog is selected from the group consisting of T1-11, JMF1907, JMF1998, JMF2665, and CGS21680. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the adenosine analog is administered in combination with a further active agent for treating pain, wherein the further active agent is different from the adenosine analog. 
     
     
         21 - 26 . (canceled)