HIGH-AFFINITY OF SIGMA(1)-BINDING SITES FOR STEROL ISOMERIZATION INHIBITORS - EVIDENCE FOR A PHARMACOLOGICAL RELATIONSHIP WITH THE YEAST STEROL C-8-C-7 ISOMERASE

1 The sigma-drug binding site of guinea-pig liver is carried by a prot ein which shares significant amino acid sequence similarities with the yeast sterol C-8-C-7 isomerase (ERG2 protein). Pharmacologically - bu t not structurally - the sigma(1)-site is also related to the emopamil binding protein, the mammalian sterol C-8-C-7 isomerase. We therefore investigated if sterol C-8-C-7 isomerase inhibitors are high affinity ligands for the (+)-[H-3]-pentazocine labelled sigma(1)-binding site. 2 Among the compounds which bound with high affinity to native hepati c and cerebral as well as to yeast expressed sigma(1)-binding sites we re the agricultural fungicide fenpropimorph (K-i 0.005 nM), the antihy pocholesterinaemic drugs triparanol (K-i 7.0 nM), AY-9944 (K-i 0.46 nM ) and MDL28,815 (K-i 0.16 nM), the enantiomers of the ovulation induce r clomiphene (K-i 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (K-i 26 nM). 3 Except for tamoxifen these affinities are ess entially identical with those for the [H-3]-ifenprodil labelled sterol C-8-C-7 isomerase of S. cerevisiae. This demonstrates that sigma(1)-b inding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma(1)-binding site is localized on a sterol isomerase related protein, involved in postsq ualene sterol biosynthesis.