General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at theGABA(A) receptor but not with lipid solubility

A series of 27 analogs of the general anesthetic propofol (2,6-diisopropylp henol) were examined for general anesthetic activity in Xenopus laevis tadp oles and for the ability to produce enhancement of submaximal GABA response s and/or direct activation at recombinant GABA(A) receptors. Fourteen of th e propofol analogs produced loss of righting reflex in the tadpoles, wherea s 13 were inactive as anesthetics. The same pattern of activity was noted w ith the actions of the compounds at the GABA(A) alpha (1)beta (2)gamma (2)s receptor. The potencies of the analogs as general anesthetics in tadpoles correlated better with potentiation of GABA responses than direct activatio n at the GABA(A) alpha (1)beta (2)gamma (2)s receptor. The calculated octan ol/water partition coefficients for the analogs did not explain the lack of activity exhibited by the 13 nonanesthetic analogs, although this physicoc hemical parameter did correlate modestly with in vivo anesthetic potency. T he actions of one nonanesthetic analog, 2,6-di-tert-butylphenol, were exami ned in detail. 2,6-Ditert-butylphenol was inactive at GABA(A) receptors, di d not function as an anesthetic in the tadpoles, and did not antagonize any of the actions of propofol at GABA(A) receptors or in tadpoles. A key infl uence on the potency of propofol analogs appears to be the size and shape o f the alkyl groups at positions 2 and 6 of the aromatic ring relative to th e substituent at position 1. These data suggest steric constraints for the binding site for propofol on the GABA(A) receptor.