Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease.

Korth C; May BC; Cohen FEPrusiner SB

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Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease.

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Prion diseases in humans and animals are invariably fatal. Prions are composed of a disease-causing isoform (PrP(Sc)) of the normal host prion protein (PrP(C)) and replicate by stimulating the conversion of PrP(C) into nascent PrP(Sc). We report here that tricyclic derivatives of acridine and phenothiazine exhibit half-maximal inhibition of PrP(Sc) 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 PrP(Sc) 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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2001年第17期|9836-9841|共6页
作者
Korth C; May BC; Cohen FEPrusiner SB;
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作者单位

Institute for Neurodegenerative Diseases, University of California, San Francisco 94143, USA.;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Acridines; Phenothiazines; PrPSc Proteins drug effects; Prion Diseases; Fatty Acids; 吖啶类; 酚噻嗪类; 朊病毒病;

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Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease.

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