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

Abstract

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 3 alpha-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-[H-3] butylbicycloorthobenzoate as radiolabeled ligand for the GABA(A) receptor. The activity of compound 4 was similar to that of allopregnanolone (1). 1 alpha, 11 alpha-Epoxypregnanolone (6) was more active than pregnanolone.