Inhibitors of ABC drug transporters at the blood-brain barrier

Abstract

The present invention relates to inhibitors of drug transporters of the ABC protein superfamily, particularly transporters present at the blood brain barrier. ABC transporter inhibitors identified according to the invention increase brain concentrations of CNS-active agents. Such inhibitors increase the influx into the brain and/or reduce the efflux from the brain of such CNS-active agents.

1 - 186 . (canceled)  
   
   
       187 . A method of inhibiting a P-glycoprotein in a subject comprising administering to the subject a P-glycoprotein inhibiting amount of an inhibitor of an ABC drug transporter, wherein the inhibitor is selected from the group consisting of naltrexone, naloxone and nalmefene, 
 wherein the inhibitor is administered before, with, or after the administration to the subject of a therapeutically effective amount of a non-opioid CNS-active agent.    
   
   
       188 . The method of  claim 187 , wherein the inhibitor is a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein R 1  is CH 2  or O;  
       wherein R 2  is a cycloalkyl, unsubstituted aromatic, alkyl or alkenyl; and  
       wherein R 3  is O, CH 2  or NH.  
     
   
   
       189 - 361 . (canceled)  
   
   
       362 . A composition comprising 
 (a) a non-opioid CNS-active agent; and    (b) an opioid receptor antagonist.    
   
   
       363 . The composition of  claim 362 , wherein the opioid receptor antagonist is a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein R 1  is CH 2  or O;  
       wherein R 2  is a cycloalkyl, unsubstituted aromatic, alkyl or alkenyl; and  
       wherein R 3  is O, CH 2  or NH.  
     
   
   
       364 . A composition comprising 
 (a) a non-opioid CNS-active agent; and    (b) an opioid inhibitor of an ABC drug transporter.    
   
   
       365 . The composition of  claim 364 , wherein the ABC drug transporter is a PGP drug transporter.  
   
   
       366 . The composition of  claim 365 , wherein the PGP drug transporter is a PGP1a drug transporter.  
   
   
       367 . The composition of  claim 364 , wherein the opioid inhibitor is an opioid receptor antagonist.  
   
   
       368 . The composition of  claim 367 , wherein the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, and nalmefene.  
   
   
       369 . The composition of  claim 364 , wherein the inhibitor is a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein R 1  is CH 2  or O;  
       wherein R 2  is a cycloalkyl, unsubstituted aromatic, alkyl or alkenyl; and  
       wherein R 3  is O, CH 2  or NH.  
     
   
   
       370 - 372 . (canceled)  
   
   
       373 . A composition comprising: 
 (a) a non-opioid CNS-active agent, and    (b) an opioid receptor antagonist that is an inhibitor of an ABC drug transporter, wherein the composition is for the treatment of chronic pain, for controlling pain without dependence, tolerance, or withdrawal.    
   
   
       374 . The composition of  claim 373 , wherein the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, and nalmefene.  
   
   
       375 . The composition of  claim 373 , wherein the non-opioid CNS-active agent is selected from the group consisting of valium, lithium, halcyon, and ambien.  
   
   
       376 . The composition of  claim 373 , wherein the opioid receptor antagonist is a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein R 1  is CH 2  or O;  
       wherein R 2  is a cycloalkyl, unsubstituted aromatic, alkyl or alkenyl; and  
       wherein R 3  is O, CH 2  or NH.  
     
   
   
       377 - 393 . (canceled)