NR AGSF
AU Korth,C.; May,B.C.H.; Cohen,F.E.; Prusiner,S.B.
TI Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease
QU Proceedings of the National Academy of Sciences of the United States of America 2001 Aug 14; 98(17): 9836-41
PT journal article
AB Prion diseases in humans and animals are invariably fatal. Prions are composed of a disease-causing isoform (PrPsc) of the normal host prion protein (PrPc) and replicate by stimulating the conversion of PrPc into nascent PrPsc. We report here that tricyclic derivatives of acridine and phenothiazine exhibit half-maximal inhibition of PrPsc formation at effective concentrations (EC(50)) between 0.3 microM and 3 microM in cultured cells chronically infected with prions. The EC(50) for chlorpromazine was 3 microM, whereas quinacrine was 10 times more potent. A variety of 9-substituted, acridine-based analogues of quinacrine were synthesized, which demonstrated variable antiprion potencies similar to those of chlorpromazine and emphasized the importance of the side chain in mediating the inhibition of PrPsc formation. Thus, our studies show that tricyclic compounds with an aliphatic side chain at the middle ring moiety constitute a new class of antiprion reagents. Because quinacrine and chlorpromazine have been used in humans for many years as antimalarial and antipsychotic drugs, respectively, and are known to pass the blood-brain barrier, we suggest that they are immediate candidates for the treatment of Creutzfeldt-Jakob disease and other prion diseases.
MH Acridines/chemistry/pharmacology/*therapeutic use; Animal; Cells, Cultured/drug effects; Chlorpromazine/chemistry/pharmacology; Comparative Study; Fatty Acids/chemistry; Human; Mice; Neuroblastoma/pathology; Phenothiazines/chemistry/pharmacology/*therapeutic use; PrPsc Proteins/*drug effects; Prion Diseases/*drug therapy; Protein Conformation/drug effects; Quinacrine/chemistry/pharmacology; Safety; Structure-Activity Relationship; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Time Factors; Tumor Cells, Cultured
AD Institute for Neurodegenerative Diseases, University of California, San Francisco 94143, USA
SP englisch
PO USA