title: Structure-activity relationship study around guanabenz identifies two derivatives retaining antiprion activity but having lost α2-adrenergic receptor agonistic activity.
abstract: 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.
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale , Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 29200 Brest, France.
authors.forename: Phu Hai
authors.initials: PH
authors.lastname: Nguyen
authors.forename: Hassan
authors.initials: H
authors.lastname: Hammoud
authors.forename: Sophie
authors.initials: S
authors.lastname: Halliez
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Pang
authors.forename: Justine
authors.initials: J
authors.lastname: Evrard
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.forename: Suparna
authors.initials: S
authors.lastname: Sanyal
authors.forename: Vincent
authors.initials: V
authors.lastname: Beringue
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bihel
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D002531:Cerebellum / Q000187:drug effects / Q000503:physiopathology; D003412:Cricetulus; D004926:Escherichia coli; D006143:Guanabenz / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy / Q000503:physiopathology; D011328:Prions / Q000187:drug effects*; D017510:Protein Folding / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D046509:Tissue Culture Techniques; D015003:Yeasts
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D018696:Neuroprotective Agents; D018620:PrPSc Proteins; D011328:Prions; D018341:Receptors, Adrenergic, alpha-2; D006143:Guanabenz
keywords: Antiprion compounds; PrPSc prion protein; guanabenz; structure−activity relationship study; yeast model for prion diseases; α2-adrenergic agonist