Tetrahydroisoquinoline alkaloid derivatives Inhibit 7-Dehydrocholesterol reductase

We prepared new phenethyltetrahydroisoquinolines, derivatives of plant isoquinoline alkaloids. Several of the compounds showed a strong and selective inhibition of 7-dehydrocholesterol reductase (7-DHCR), an enzyme responsible for the conversion of 7-DHC to cholesterol in the last step of cholesterol biosynthesis. A defect of 7-DHCR is associated with the Smith-Lemli-Opitz syndrome (SLOS), a known autosomal recessive trait accompanied by severe abnormalities. Our investigations led to the discovery of 1 as a selective and 200 times stronger inhibitor of 7-DHCR than the established less selective inhibitor BM 15.766. The isoquinoline 1 had no effect on ergosterol biosynthesis in fungi and displayed very low cytotoxicity. The new inhibitor of 7-DHCR will be a useful tool for studying molecular details of the pathogenesis of SLOS.