Parallel artificial membrane permeability assay for blood-brain barrier (PAMPA-BBB) of tacrine-donepezil hybrids as potential anti-Alzheimer's drugs

• Grant number: 14/10414-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: November 03, 2014
• End date: July 05, 2015
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ivone Carvalho
• Grantee: Talita Perez Cantuaria Chierrito
• Supervisor: Ana Martinez Gil
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Centro de Investigaciones Biológicas (CIB), Spain
• Associated to the scholarship: 12/04054-5 - Synthesis of potential acetylcholinesterase inhibitor for treating Alzheimer's Disease, BP.DR

Abstract

Alzheimer´s disease (AD) is a process involving progressive and irreversible decline of cognitive functions which leads to disorganization of the behavior and psychotic symptoms. The World Health Organization estimates that in 20 years, mental illness and neurological disorders will be the second cause of death worldwide. It is observed in the brains of AD individuals: diffuse cortical atrophy, the presence of numerous senile plaques, neurofibrillary tangles, and neuronal loss. Alzheimer's disease is complex and the current therapeutic approaches for the treatment of AD provides only transient and limited benefit for the patients, therefore, in response to molecular complexity of the disease, the search for alternative drugs for the treatment of AD is relevant. The current project is focused on the design, synthesis of tacrine-donepezil hybrids (both acetylcholinesterase inhibitors drugs) to provide a treatment for AD. Promising CNS (central nervous system) drugs as well as anti-Alzheimer need to present the ability to cross the blood-brain barrier (BBB) and reach the therapeutics targets. BBB is a highly selective permeability barrier formed by capillary endothelial cells, which are connected by tight junctions in order to keep the homeostasis of this microenvironment. Focused on this required property for CNS drugs, the present proposal aims the evaluation of the synthesized tacrine-donepezil hybrids using the parallel artificial membrane permeability assay (PAMPA) to predict the BBB penetration, PAMPA-BBB is a validated method which employs a brain lipid porcine membrane. So with the help of neurodegenerative diseases expertise group from Consejo Superior de Investigaciones Científicas (CSIC-Spain), we will learn and apply this methodology to evaluate the compounds prepared in the thesis (FAPESP n. 2012/040545 and FAPESP/CSIC n. 2013/50788-3). (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CHIERRITO, TALITA P. C.; PEDERSOLI-MANTOANI, SUSIMAIRE; ROCA, CARLOS; SEBASTIAN-PEREZ, VICTOR; MARTINEZ-GONZALEZ, LORETO; PEREZ, DANIEL I.; PEREZ, CONCEPCION; CANALES, ANGELES; JAVIER CANADA, F.; CAMPILLO, NURIA E.; et al. Chameleon-like behavior of indolylpiperidines in complex with cholinesterases targets: Potent butyrylcholinesterase inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 145, p. 431-444, FEB 10 2018. (14/10414-0, 13/50788-3, 12/14114-5, 12/04054-5)