Conformationally constrained anesthetic steroids that modulate GABAA receptors

Various cyclic ether and other 3 alpha -hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [S-35]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha -hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha -hydroxypregnan-20-ones all had an ether oxygen on the beta -face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta -face of the steroid.