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

The sigma‐drug binding site of guinea‐pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C 8 –C 7 isomerase (ERG2 protein). Pharmacologically ‐ but 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 (+)‐[ 3 H]‐pentazocine labelled sigma 1 ‐binding site. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma 1 ‐binding sites were the agricultural fungicide fenpropimorph ( K i 0.005 n M ), the antihypocholesterinaemic drugs triparanol ( K i 7.0 n M ), AY‐9944 ( K i 0.46 n M ) and MDL28,815 ( K i 0.16 n M ), the enantiomers of the ovulation inducer clomiphene ( K i 5.5 and 12 n M , respectively) and the antioestrogene tamoxifen ( K i 26 n M ). Except for tamoxifen these affinities are essentially identical with those for the [ 3 H]‐ifenprodil labelled sterol C 8 –C 7 isomerase of S. cerevisiae . This demonstrates that sigma 1 ‐binding 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 postsqualene sterol biosynthesis.British Journal of Pharmacology (1997) 121 , 1–6; doi: 10.1038/sj.bjp.0701079