Synthesis and use of the n-bromododecane-1,12-diols as conformational probes for general anesthetic target sites.
The n-bromododecane-1,12-diols with bromine on carbons 2, 3, 5, and 6, respectively, were synthesized and found to be potent general anesthetics. They were also found to be potent inhibitors of firefly luciferase, a protein model for the primary target sites underlying general anesthesia. However, their effects on lipid bilayers were small, lowering the chain-melting phase transition temperature by less than 1 degree C at their EC50 concentrations for general anesthesia. A large dependence upon the position of the bromine atom was found for both n-hexadecane/water partition coefficients and inhibition constants for firefly luciferase; a much smaller positional dependence was found for induction of general anesthesia and for disrupting lipids. These results are consistent with the bulky bromine atom inhibiting the conformational flexibility of the diol hydrocarbon chain, making these bromo diols useful probes for ascertaining the shapes of apolar binding sites. In particular, our measurements suggest that these novel anesthetics produce general anesthesia by binding to long and relatively narrow apolar target sites in the central nervous system.
Dickinson
R
R
Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, U.K.
Smith
E H
EH
Franks
N P
NP
Lieb
W R
WR
D000768:Anesthesia, General; D000777:Anesthetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001517:Coleoptera; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007536:Isomerism; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D011896:Rana temporaria; D013329:Structure-Activity Relationship
D000777:Anesthetics; D006842:Hydrocarbons, Brominated; D008156:Luciferases