Structure-Activity Relationship Study around Guanabenz Identifies Two Derivatives Retaining Antiprion Activity but Having Lost α2-Adrenergic Receptor Agonistic Activity
Structure-Activity Relationship Study around Guanabenz Identifies Two Derivatives Retaining Antiprion Activity but Having Lost α2-Adrenergic Receptor Agonistic Activity
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DOI：
10.1021/cn5001588
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发表时间：
2014-10-01
影响因子：
5
通讯作者：
Voisset, Cecile
中科院分区：
文献类型：
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作者：
Phu Hai Nguyen;Hammoud, Hassan;Voisset, Cecile
Guanabenz （GA）是一种口服活性α 2-肾上腺素能激动剂，多年来一直用于治疗高血压。我们最近描述了GA对酵母和哺乳动物朊病毒也有活性，以不依赖于α 2-肾上腺素能受体的方式。这些数据表明，GA的这种副活性可以用于朊病毒疾病和其他淀粉样蛋白疾病的治疗。从这个角度来看，GA的有效降压活性恰好是一个令人讨厌的副作用，可能会限制其使用。为了消除GA在α 2-肾上腺素能受体上的激动剂活性，我们通过改变GA苯基团上氯的位置，然后对其胍基进行修饰，对GA进行了构效关系研究。因此，我们确定了两个衍生物6和7仍然具有有效的抗朊病毒活性，但在α 2-肾上腺素能受体上完全缺乏任何激动剂活性。与GA类似，6和7也能够抑制核糖体（PFAR）的蛋白质折叠活性，这被认为与朊病毒的出现/维持有关。因此，这两种GA衍生物值得考虑作为候选药物。
Guanabenz (GA) is an orally active alpha 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 alpha 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 alpha 2-adrenergic receptors, we performed a structure-activity 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 alpha 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.