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Vol. 297, Issue 1, 338-351, April 2001
-Aminobutyric Acid (GABA)
Current at the GABAA Receptor but Not with Lipid Solubility
Department of Anesthesiology, Weill Medical College of Cornell
University, New York City, New York (A.J., N.L.H.); Department of
Anesthesia and Critical Care (M.D.K., A.Y.K.) and the Committee on
Neurobiology (M.D.K.), University of Chicago, Chicago, Illinois;
Department of Anesthesiology, Columbia University, New York City, New
York (P.F.); and Laboratory of Molecular Modeling and Design, College
of Pharmacy, University of Illinois at Chicago, Chicago, Illinois
(A.J.H.)
A series of 27 analogs of the general anesthetic propofol
(2,6-diisopropylphenol) were examined for general anesthetic activity in Xenopus laevis tadpoles and for the ability to
produce enhancement of submaximal GABA responses and/or direct
activation at recombinant GABAA receptors. Fourteen of the
propofol analogs produced loss of righting reflex in the tadpoles,
whereas 13 were inactive as anesthetics. The same pattern of activity
was noted with the actions of the compounds at the GABAA
1
2
2s receptor. The
potencies of the analogs as general anesthetics in tadpoles correlated
better with potentiation of GABA responses than direct activation at the GABAA 122s
receptor. The calculated octanol/water partition coefficients for the
analogs did not explain the lack of activity exhibited by the 13 nonanesthetic analogs, although this physicochemical parameter did
correlate modestly with in vivo anesthetic potency. The actions of one
nonanesthetic analog, 2,6-di-tert-butylphenol, were
examined in detail. 2,6-Di-tert-butylphenol was inactive at GABAA receptors, did not function as an anesthetic in
the tadpoles, and did not antagonize any of the actions of propofol at
GABAA receptors or in tadpoles. A key influence on the
potency of propofol analogs appears to be the size and shape of the
alkyl groups at positions 2 and 6 of the aromatic ring relative to the
substituent at position 1. These data suggest steric constraints for
the binding site for propofol on the GABAA receptor.
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