Huprine鈥揟acrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer鈥檚 and Prion Diseases

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• 作者：Carles Galdeano ; Elisabet Viayna ; Irene Sola ; Xavier Formosa ; Pelayo Camps ; Albert Badia ; M. Vict貌ria Clos ; J煤lia Relat ; M铆riam Ratia ; Manuela Bartolini ; Francesca Mancini ; Vincenza Andrisano ; Mario Salmona ; Cristina Minguill贸n ; Gema C. Gonz谩lez-Mu帽oz ; M. Isabel Rodr铆guez-Franco ; Axel Bidon-Chanal ; F. Javier Luque ; Diego Mu帽oz-Torrero
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：661-669
• 全文大小：331K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

A family of huprine鈥搕acrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the 尾-amyloid peptide (A尾) and a prion peptide with a key role in the aggregation of the prion protein. Huprine鈥搕acrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced A尾 aggregation, and 尾-secretase. Finally, they are able to cross the blood鈥揵rain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer鈥檚 and prion diseases.