Conformationally constrained anesthetic steroids that modulate GABA(A) receptors

Various cyclic ether and other 3 alpha -hydroxyandrostane derivatives beari ng a conformationally constrained hydrogen-bonding moiety were prepared. Th eir anesthetic potency and their binding affinity for GABA(A) receptors, me asured by intravenous administration to mice and inhibition of [S-35]TBPS b inding to rat whole brain membranes, were compared with that of known anest hetic 3 alpha -hydroxypregnan-20-ones. Synthetic steroids with similar in v itro and in vivo activities to the endogenous 3 alpha -hydroxypregnan-20-on es all had an ether oxygen on the beta -face of the steroid D-ring. These r esults suggest that for optimal GABA(A) receptor modulation, the hydrogen b ond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta -face of the steroid.