Structure鈥揂ctivity Relationship Study around Guanabenz Identifies Two Derivatives Retaining Antiprion Activity but Having Lost 伪2-Adrenergic Receptor Agonistic Activity
详细信息 查看全文
- 作者：Phu hai Nguyen ; Hassan Hammoud ; Sophie Halliez ; Yanhong Pang ; Justine Evrard ; Martine Schmitt ; Nassima Oumata ; Jean-Jacques Bourguignon ; Suparna Sanyal ; Vincent Beringue ; Marc Blondel ; Fr茅d茅ric Bihel ; C茅cile Voisset
- 刊名：ACS Chemical Neuroscience
- 出版年：2014
- 出版时间：October 15, 2014
- 年：2014
- 卷：5
- 期：10
- 页码：1075-1082
- 全文大小：331K
- ISSN：1948-7193
文摘
Guanabenz (GA) is an orally active 伪2-adrenergic agonist that has been used for many years for the treatment of hypertension. We recently described that GA is also active against both yeast and mammalian prions in an 伪2-adrenergic receptor-independent manner. These data suggest that this side-activity of GA could be explored for the treatment of prion-based diseases and other amyloid-based disorders. In this perspective, the potent antihypertensive activity of GA happens to be an annoying side-effect that could limit its use. In order to get rid of GA agonist activity at 伪2-adrenergic receptors, we performed a structure鈥揳ctivity relationship study around GA based on changes of the chlorine positions on the benzene moiety and then on the modifications of the guanidine group. Hence, we identified the two derivatives 6 and 7 that still possess a potent antiprion activity but were totally devoid of any agonist activity at 伪2-adrenergic receptors. Similarly to GA, 6 and 7 were also able to inhibit the protein folding activity of the ribosome (PFAR) which has been suggested to be involved in prion appearance/maintenance. Therefore, these two GA derivatives are worth being considered as drug candidates.