Analgesic screening method and composition

Abstract

Disclosed is a method of selecting analgesic agents based on their selective ability to block tetrodotoxin-insensitive sodium channels, particularly in comparison to blocking tetrodotoxin-sensitive sodium channels. Also disclosed is a novel class of compounds that is selective for blocking tetrodotoxin-insensitive sodium channels.

It is claimed:  
     
         1 . A method of selecting a compound for use in producing analgesia in a subject, comprising 
 measuring the ability of said compound to block tetrodotoxin-insensitive (TTXi) sodium channels and to block tetrodotoxin-sensitive (TTXs) sodium channels, and    selecting the compound if (i) it exhibits a potency in blocking TTXi sodium channels that is at least about one-tenth as great as the potency exhibited by 3-hydroxy monoethylglycinexylidide in blocking said TTXi sodium channels, and (ii) it exhibits a potency ratio of at least 2 in blocking said TTXi sodium channel as compared to blocking said TTXs sodium channel.    
     
     
         2 . The method of  claim 1 , wherein said compound is selected if its potency in inhibiting said TTXi sodium channels is at least as great as that of 3-hydroxy monoethylglycinexylidide in blocking said channels.  
     
     
         3 . The method of  claim 1 , wherein said potency ratio of blocking said TTXi and said TTXs sodium channels measured by the formula: 1/(IC 50, TTXi /IC 50, TTXi ) where IC 50, TTXi  is the concentration of compound effective to inhibit current through said tetrodotoxin-insensitive sodium channel by 50%, and IC 50, TTXs  is the concentration of said compound effective to inhibit current through said tetrodotoxin-sensitive sodium channel by 50%.  
     
     
         4 . The method of  claim 1 , wherein said compound is further monitored for its ability to reversibly block said TTXi sodium channel in a cell bathing solution in an electrophysiological assay of tetrodotoxin-insensitive sodium channels and is selected if not more than 5-15% of a sodium current that passes through said TTXi sodium channel recovers after said compound is removed from said cell bathing solution.  
     
     
         5 . The method of  claim 1 , wherein said measuring of tetrodotoxin-insensitive sodium channel blockade is by electrophysiological means.  
     
     
         6 . The method of  claim 1 , wherein said measuring of tetrodotoxin-insensitive sodium channel blockade is carried out in a ligand displacement assay.  
     
     
         7 . The method of  claim 6 , wherein said ligand is 3-hydroxy monoethylglycinexylidide.  
     
     
         8 . An analgesic composition, comprising a 3-hydroxy monoethylglycinexylidide analog that (i) is effective to block TTXi sodium channels with a potency that is at least about one-tenth as great as the potency exhibited by 3-hydroxy monoethylglycinexylidide in blocking said channels, and (ii) exhibits a potency ratio of at least 2 in blocking said TTXi sodium channels as compared to blocking TTXs sodium channels.  
     
     
         9 . The analgesic composition of  claim 7 , wherein said analog blocks said TTXi sodium channels with a potency that is at least as great as the potency exhibited by 3-hydroxy monoethylglycinexylidide in blocking said channels.