Evidence that there is no direct correlation between alpha 2-adrenoceptor antagonism and inhibition of voltage-dependent sodium channels.

Electrophysiological and biochemical evidence suggests that the voltage-dependent sodium channel is the site of local anesthetic action, and that there is pharmacological similarity between alpha-adrenoceptors and Na+-channels. Yohimbine, a non-selective alpha 2-adrenoceptor antagonist, with a structure similar to that of cocaine affects the sodium channel by a mechanism different from that of other local anesthetics including cocaine. Some structural analogues of yohimbine -berbane compounds- were found to be potent and selective alpha 2-adrenoceptor antagonists. In this work the local anesthetic properties of two berbane compounds (6c and 6d (CH-38083) from the paper of Vizi, Toth, Somogyi, Szabo, Harsing and Szantay, 1987) were examined and compared to those of yohimbine in vitro on scorpion venom-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate [( 3H]BTX-B) to the voltage-sensitive sodium channel and on the veratridine-induced depolarization measured by the uptake of [3H]trimethylphenylphosphonium ion [( 3H]TPMP+) in mouse brain cortex. Both of the compounds inhibited the [3H]BTX-B binding with an IC50 of (approximately) 150 microM, which is more than four orders of magnitude higher than the concentration required for antagonism of a presynaptic alpha 2-adrenoceptor (7 nM). They are 15 times less potent in inhibiting [3H]BTX-B binding and 2.5 times less potent in inhibiting veratridine-induced depolarization than yohimbine.