Abstract
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 GABAAα1β2γ2s receptor. The potencies of the analogs as general anesthetics in tadpoles correlated better with potentiation of GABA responses than direct activation at the GABAA α1β2γ2sreceptor. 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.
Footnotes
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Send reprint requests to: Neil L. Harrison, Ph.D., Director, Laboratory of Molecular Neuropharmacology, Department of Anesthesiology, A-1050, Weill Medical College of Cornell University, 525 East 68th St., New York, NY 10021. E-mail:neh2001{at}med.cornell.edu
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This study was funded by the C. V. Starr Foundation (New York City, NY) and the Rice Foundation (Chicago, IL) to N.L.H., by National Institutes of Health Grants GM56850 and GM62195 to N.L.H. and K08-GM00695 to P.F., by National Institute of Mental Health training fellowship MH11504 to M.D.K., and by the Procter and Gamble Company and The Chem21 Group, Inc., to A.J.H.
- Abbreviations:
- GABAA
- γ-aminobutyric acid type A
- SAR
- structure-activity relationship
- PIPES
- piperazine-N,N′-bis[2-ethanesulfonic acid]
- cDNA
- complimentary DNA
- HEK
- human embryonic kidney
- log P
- log10 of the octanol/water partition coefficient
- Received August 18, 2000.
- Accepted January 9, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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