From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer's disease

Autor(es):Mostrar menos -

Chierrito, Talita P. C. ^[1] ; Pedersoli-Mantoani, Susimaire ^[1] ; Roca, Carlos ^[2] ; Requena, Carlos ^[2] ; Sebastian-Perez, Victor ^[2] ; Castillo, Willian O. ^[3] ; Moreira, Natalia C. S. ^[3] ; Perez, Concepcion ^[4] ; Sakamoto-Hojo, Elza T. ^{[3, 5]} ; Takahashi, Catarina S. ^{[3, 5]} ; Jimenez-Barbero, Jesus ^{[2, 6]} ; Javier Canada, F. ^[2] ; Campillo, Nuria E. ^[2] ; Martinez, Ana ^[2] ; Carvalho, Ivone ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] CSIC, Ctr Invest Biol, IPSBB Unit, Ramiro de Maeztu 9, Madrid 28040 - Spain

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] CSIC, Inst Quim Med, Juan Cierva 3, E-28006 Madrid - Spain

^[5] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Biol, Ave Bandeirantes 3900, BR-14040900 Ribeirao Preto, SP - Brazil

^[6] CIC BioGUNE, Parque Tecnol Bizkaia, Edif 801A, Bilbao 48160 - Spain

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 139, p. 773-791, OCT 20 2017.
• Citações Web of Science: 10

Resumo

The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD. (C) 2017 Elsevier Masson SAS. All rights reserved. (AU)

• Processo FAPESP: 13/50788-3 - Novos e potenciais agentes anti-Alzheimer: do planejamento aos estudos clínicos
• Beneficiário: Ivone Carvalho
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/04054-5 - Síntese de potencial inibidor de acetilcolinesterase para tratamento da Doença de Alzheimer
• Beneficiário: Talita Perez Cantuaria Chierrito
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/14114-5 - Planejamento, síntese e avaliação de inibidores duplos de acetilcolinesterase como potenciais candidatos a fármacos anti-Alzheimer
• Beneficiário: Ivone Carvalho
• Linha de fomento: Auxílio à Pesquisa - Regular