NEUROSTEROID ANALOGS - 6 - THE SYNTHESIS AND GABA(A) RECEPTOR PHARMACOLOGY OF ENANTIOMERS OF DEHYDROEPIANDROSTERONE-SULFATE, PREGNENOLONE SULFATE, AND (3-ALPHA,5-BETA)-3-HYDROXYPREGNAN-20-ONE SULFATE

The unnatural enantiomers of dehydroepiandrosterone sulfate (1), pregn enolone sulfate (2), and (3 alpha,5 beta)-3-hydroxypregnan-20-one sulf ate (3), compounds 4-6, respectively, were prepared by total steroid s ynthesis. The enantioselectivity of the compounds as negative modulato rs of the GABA(A) receptors present in cultured rat hippocampal neuron s was examined using electrophysiological methods. Enantioselectivity was found for the inhibitory actions of the dehydroepiandrosterone ena ntiomers, The IC(50)s for compounds 1 and 4 were 11 +/- 1 and 80 +/- 1 4 mu M, respectively. Little, if any, enantioselectivity was found for the other two pairs of steroid sulfate inhibitors. The IC(50)s for co mpounds 2 and 5 were 82 +/- 12 and 76 +/- 27 mu M, respectively. The I C(50)s for compounds 3 and 6 were 39 +/- 7 and 46 +/- 2 mu M, respecti vely. The results suggest that the sites of action for the androstane and pregnane series of steroid sulfate blockers of GABA-mediated curre nt are different. The observed enantioselectivity for the actions of d ehydroepiandrosterone sulfate indicates that its inhibitory actions ar e mediated via a chiral recognition site and provides new evidence in support of the earlier hypothesis that there is a binding site for thi s compound on GABA(A) receptors. Conversely, the failure to observe en antioselectivity for the actions of pregnenolone sulfate and steroid s ulfate 3 indicates that a chiral recognition site far these steroids d oes not exist on GABA(A) receptors and suggests that the effects of th ese compounds on this receptor's function may arise indirectly as a co nsequence of steroid-induced membrane perturbation.