The Journal of General Physiology, Vol 96, 1105-1127, Copyright © 1990 by The Rockefeller University Press
Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels
GK Wang
Department of Anesthesia Research Laboratories, Harvard Medical School, Boston, Massachusetts.
Several local anesthetics (LA) have been previously shown to block muscle
batrachotoxin (BTX)-activated Na+ channels in planar bilayers. The mean
dwell time of different LA drugs, however, varies widely, from less than 10
ms to longer than several seconds. In this study, we have examined the
structural determinants that govern the dwell time, the binding affinity,
and the stereoselectivity of LA drugs using cocaine and bupivacaine
homologues, RAC compounds, and their available stereoisomers. Our results
from the structure-activity experiments reveal that (a) there are two
apparent hydrophobic binding domains present in the LA binding site; one
interacts with the aromatic moiety of the LA drugs, and the other interacts
with the alkyl group attached to the tertiary amine of the LA drugs; (b)
the LA mean dwell time and the binding affinity are largely determined by
the hydrophobic interactions; (c) the LA binding site is highly
stereoselective, with a difference in KD values over 50- and 6-fold for
(+/-) cocaine and (+/-) bupivacaine, respectively; (d) the cocaine
stereoselectivity is comparable among muscle, brain, and heart
BTX-activated Na+ channels; and finally and most unexpectedly, (e) the
stereoselectivity of LA drugs in BTX-activated Na+ channels appears greatly
different from that reported in normal Na+ channels. Possible explanations
for this difference are discussed.
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