Interactions of cocaine and cocaine congeners with sodium channels.

To assess the role that action on sodium channels may play in the physiological effects of cocaine and to obtain information on the structure-activity relationships of this action, cocaine, norcocaine, N-allynorcocaine, (+)-pseudococaine, (-)-pseudococaine, (+/-)-allococaine, (+/-)-allopseudococaine, ecgonine, ecgonine methyl ester, O-benzoylecgonine and atropine were tested for their effects on sodium channels. The method employed was a sodium channel specific equilibrium 22Na+ uptake assay with rat brain membrane homogenates. All of the compounds listed with the exception of the ecgonines were found to be single affinity competitive inhibitors of veratridine activation of sodium channels. Ecgonine showed no inhibition at concentrations as high as 10(-3) M while ecgonine methyl ester and O-benzoylecgonine showed inhibition only at very high concentrations. The order of inhibition potencies was found to (+)-pseudococaine congruent to norcocaine congruent to N-allynorcocaine greater than cocaine greater than (-)-pseudococaine congruent to (+/-)-allopseudococaine greater than (+/-)-allococaine greater than atropine greater than O-benzoylecgonine greater than ecgonine methyl ester greater than ecgonine. This ordering of potencies is in good agreement with published reports of the local anesthetic potencies of these agents.