Planta Med 2012; 78 - PD129
DOI: 10.1055/s-0032-1320487

Tetrahydroisoquinoline alkaloid derivatives Inhibit 7-Dehydrocholesterol reductase

A Horling 1, C Müller 2, F Bracher 2, P Imming 1
  • 1Martin-Luther-Universitaet Halle-Wittenberg, Institut fuer Pharmazie, Wolfgang-Langenbeck-Strasse 4, 06120 Halle, Germany
  • 2Ludwig-Maximilians-Universitaet Muenchen, Department Pharmazie, Butenandtstrasse 5, 81377 Muenchen, Germany

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.