To study the local anesthetic properties of yohimbine in more detail, its effect was examined in vitro on the scorpion toxin-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate [( 3H]BTX-B) to the gating complex in sodium channel preparations from mouse brain cortex. Both equilibrium and kinetic experiments were carried out. Yohimbine inhibited the specific binding of [3H]BTX-B in the vesicular preparation with an IC50 value of 2.2 X 10(-5) M. This is about one order of magnitude higher than the concentration required for antagonism via the alpha 2-adrenoceptors; however, yohimbine is 7-fold more potent in inhibiting [3H]BTX-B binding than lidocaine. In a concentration-dependent manner, yohimbine increased the dissociation constant (Kd) of high-affinity [3H]BTX-B binding without changing the maximal binding capacity (Bmax). The dissociation rate constant was not affected by yohimbine, suggesting competitive inhibition as opposed to the action of local anesthetics involving an allosteric action via receptor sites distinct from the BTX site. Alpha 2-adrenoceptors are apparently not involved because clonidine and alpha-methyl-noradrenaline had no appreciable effect on [3H]BTX-B binding and did not antagonize the inhibitory effect of yohimbine. The present findings indicate a mechanism of local anesthetic action of yohimbine that differs from that of other local anesthetics such as tetracaine and lidocaine involving direct binding to the BTX site, thereby stabilizing a non-permeable form of the sodium channel.
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http://dx.doi.org/10.1016/0006-2952(88)90137-2 | DOI Listing |
J Med Chem
December 2004
Department of Chemistry, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
We previously developed a preliminary 3-D QSAR model for the binding of 14 hydantoins to the neuronal voltage-gated sodium channel; this model was successful in designing an effective non-hydantoin ligand. To further understand structural features that result in optimum binding, here we synthesized a variety of compound classes and evaluated their binding affinities to the neuronal voltage-gated sodium channel using the [3H]-batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) binding assay. In order to understand the importance of the hydantoin ring for good sodium channel binding, related non-hydantoins such as hydroxy amides, oxazolidinediones, hydroxy acids, and amino acids were included.
View Article and Find Full Text PDFCell Mol Neurobiol
February 2002
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Reserpine inhibited batrachotoxin-elicited sodium influx in guinea pig brain synaptoneurosomes with an IC50 of about 1 microM. In the presence of brevetoxin the IC50 increased to about 80 microM. Reserpine inhibited binding of batrachotoxinin-A [3H]benzoate ([3H]BTX-B) binding in a complex manner causing a partial inhibition from 0.
View Article and Find Full Text PDFPest Manag Sci
October 2001
Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, V5A 1S6, Canada.
Using preparations derived from whole mouse brain, we have demonstrated that insecticidal arylalkylbenzhydrolpiperidines inhibit the depolarization of synaptoneurosomes as measured by rhodamine 6G fluorescence and block 22Na+ uptake into synaptosomes, when veratridine is used as the activator. These insecticides also have the ability to potently displace the binding of [3H]batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) to neuronal sodium channels in a concentration-dependent manner. The study compounds can be classified as competitive inhibitors of radioligand binding, since they decrease the affinity of [3H]BTX-B for site 2 without affecting the concentration of sites labelled by this radioligand.
View Article and Find Full Text PDFBr J Pharmacol
December 1996
Department of Anesthesiology, Cornell University Medical College, New York, NY 10021, USA.
1. Propofol (2,6 di-isopropylphenol), an intravenous general anaesthetic, blocks voltage-dependent Na+ channels (Na+ channels). In this study the interaction between propofol and Na+ channels was analysed by examining its effects on neurotoxin binding to various receptor sites of the Na+ channel in rat cerebrocortical synaptosomes.
View Article and Find Full Text PDFJ Neurochem
December 1996
Department of Cell and Animal Biology, Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Israel.
The delta-conotoxin-TxVIA from Conus textile (delta TxVIA) is a mollusk-specific conotoxin that slows sodium channel inactivation exclusively in mollusk neuronal membranes but reveals high-affinity binding to both mollusk (effective binding) and rat brain (silent binding) neuronal membranes, despite not having any toxic effect in vertebrates in vivo and in vitro. Using binding studies with radioactive delta TxVIA we demonstrate that a different mollusk-specific conotoxin, delta-conotoxin-GmVIA from the venom of Conus gloriamaris, possesses "silent" and effective binding properties in rat brain and mollusk sodium channels, respectively. Binding studies and electrophysiological tests with both vertebrate muscle and insect neuronal preparations have indicated that the silent binding sites of delta TxVIA are highly conserved in a wide range of distinct vertebrate and insect sodium channels.
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