Structure-Activity Relationship Study around Guanabenz Identifies Two Derivatives Retaining Antiprion Activity but Having Lost alpha 2-Adrenergic Receptor Agonistic Activity
2014 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, Vol. 5, no 10, 1075-1082 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 5, no 10, 1075-1082 p.
Antiprion compounds, guanabenz, yeast model for prion diseases, PrPSc prion protein, structure-activity relationship sudy, alpha 2-adrenergic agonist
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-236544DOI: 10.1021/cn5001588ISI: 000343276600022PubMedID: 25244284OAI: oai:DiVA.org:uu-236544DiVA: diva2:766334