Molecular pharmacology
-
Molecular pharmacology · Mar 1984
Inhibition of binding of [3H]batrachotoxinin A 20-alpha-benzoate to sodium channels by local anesthetics.
The effects of several local anesthetics on the binding of ligands to receptors associated with voltage-sensitive sodium channels in rat brain synaptosomes have been examined. In the presence of 0.3 microM scorpion toxin, the 13 local anesthetics tested inhibited the specific binding of [3H]batrachotoxinin A 20 alpha-benzoate [( 3H]BTX-B), a ligand which binds to a receptor site responsible for the activation of sodium channel ion flux, in a dose-dependent fashion, with KD values ranging from 1.2 microM for tetracaine to 1.58 mM for benzocaine. A plot of log KD from these binding experiments against log K0.5 for inhibition of sodium currents by local anesthetics from electrophysiological experiments yielded a regression line with a slope of 0.84 and a correlation coefficient, r, of 0.86, demonstrating that the inhibition of [3H]BTX-B binding by local anesthetics occurs within a concentration range of physiological relevance. ⋯ Analysis of the effects of local anesthetics in terms of an allosteric model of drug action showed that they bind to inactive states of sodium channels with at least a 10-fold higher affinity than active states. A 7-fold difference in KD for inhibition of [3H]BTX-B binding between the local anesthetic stereoisomers RAC 109 I and RAC 109 II was observed. Similarly, the dissociation rate constant for the [3H]BTX-B/receptor complex was increased 9.3-fold in the presence of RAC 109 II and 4.3-fold in the presence of a comparable concentration of RAC 109 I.(ABSTRACT TRUNCATED AT 250 WORDS)