title: Evidence that there is no direct correlation between alpha 2-adrenoceptor antagonism and inhibition of voltage-dependent sodium channels.
abstract: 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.
authors.affiliation: Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Ward's Island, New York, NY 10035.
authors.forename: I
authors.initials: I
authors.lastname: Zimanyi
authors.forename: A
authors.initials: A
authors.lastname: Lajtha
authors.forename: E S
authors.initials: ES
authors.lastname: Vizi
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: M E
authors.initials: ME
authors.lastname: Reith
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D000317:Adrenergic alpha-Antagonists; D015222:Sodium Channels