Structure-activity relationship study around guanabenz identifies two derivatives retaining antiprion activity but having lost α2-adrenergic receptor agonistic activity.
Guanabenz (GA) is an orally active α2-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 α2-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 α2-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 α2-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.
['Nguyen|Phu Hai|PH|', 'Hammoud|Hassan|H|', 'Halliez|Sophie|S|', 'Pang|Yanhong|Y|', 'Evrard|Justine|J|', 'Schmitt|Martine|M|', 'Oumata|Nassima|N|', 'Bourguignon|Jean-Jacques|JJ|', 'Sanyal|Suparna|S|', 'Beringue|Vincent|V|', 'Blondel|Marc|M|', 'Bihel|Frédéric|F|', 'Voisset|Cécile|C|']
D058647:Adrenergic alpha-2 Receptor Agonists D000818:Animals D016466:CHO Cells D002417:Cattle D002531:Cerebellum D003412:Cricetulus D004926:Escherichia coli D006143:Guanabenz D006801:Humans D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D015394:Molecular Structure D018696:Neuroprotective Agents D018620:PrPSc Proteins D017096:Prion Diseases D011328:Prions D017510:Protein Folding D018341:Receptors, Adrenergic, alpha-2 D012270:Ribosomes D013329:Structure-Activity Relationship D046509:Tissue Culture Techniques D015003:Yeasts
guanabenz α2-adrenergic agonist Antiprion compounds PrPSc prion protein structure−activity relationship study yeast model for prion diseases