Synthesis and GABA A receptor activity of oxygen-bridged neurosteroid analogs

Three analogs of neuroactive steroids were prepared ( 4– 6) in which 1,11- or 11,19-oxygen bridges give a constrained conformation. Their 3D structures were obtained by ab initio calculations and in the case of 3α-hydroxy-11,19-epoxypregn-4-ene-20-one ( 4), confirmed by X-ray analysis. Biological activity of the synthetic steroids was assayed in vitro using t-[ 3H]butylbicycloorthobenzoate as radiolabeled ligand for the GABA A receptor. The activity of compound 4 was similar to that of allopregnanolone ( 1). 1α,11α-Epoxypregnanolone ( 6) was more active than pregnanolone ( 2).