Design, computational studies, synthesis and pharmacological evaluation of novel bioactive substances against nicotinic acetylcholine receptors alpha7 and alpha4beta2

• Grant number: 18/00187-7
• Support Opportunities: Regular Research Grants
• Duration: May 01, 2018 - December 31, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Nailton Monteiro Do Nascimento Júnior
• Grantee: Nailton Monteiro Do Nascimento Júnior
• Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Jean Leandro dos Santos

Abstract

Changes involving the neuronal nicotinic acetylcholine receptors (nAChRs) are related with several diseases: schizophrenia, epilepsy, Alzheimer's disease (AD), anxiety, Parkinson's disease and the dependence caused by psychoactive substances. For instance, alchohol, nicotine, tetrahydrocannabinol and cocaine. Among the nAChRs found in the central nervous system (CNS), the subtypes alpha7 and alpha4beta2 are more abundant in comparison with the other nAChRs subtypes and ligands of these two receptors have potential as therapeutic agents. Exemplifying a relevant disease mentioned above, AD has around 7.7 million cases annually, according to World Health Organization (WHO). The nAChRs alpha7 presents neuroprotective effects, attenuating the neurotoxicity induced by beta-amyloid protein, and the modulation (by agonists) of this receptor is a promising approach for the treatment of AD. In parallel, tobacco addiction kills around 5.4 million people annually in the world and these deaths are related with the following diseases: lung cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular diseases. An alternative to treat nicotine dependence is through the modulation by partial agonists of the nAChRs alpha4beta2, which is involved directly in the dopaminergic activation and in the development of dependence. In this context, this project aims the design, computational studies involving molecular docking, synthesis and pharmacological evaluation of novel ligands of nAChRs alpha7 and alpha4beta2, through in vitro assays and function activity studies. (AU)

Scientific publications

(4)

(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)

FARIAS, R. L.; POLEZ, A. M. R.; SILVA, D. E. S.; ZANETTI, R. D.; MOREIRA, M. B.; BATISTA, V. S.; REIS, B. L.; NASCIMENTO-JUNIOR, N. M.; ROCHA, V, F.; LIMA, M. A.; et al. In vitro and in silico assessment of antitumor properties and biomolecular binding studies for two new complexes based on Ni-II bearing k(2)N, S-donor ligands. Materials Science & Engineering C-Materials for Biological Applications, v. 121, FEB 2021. (18/00187-7, 15/12098-0, 16/17711-5)

ANA BEATRIZ SILVA VELLOSA; VALDINEI BUENO LIMA FILHO; BRENO ALMEIDA SOARES; NAILTON M. NASCIMENTO-JÚNIOR. Atividade anti-Alzheimer de substâncias oriundas de produtos naturais e de origem sintética: alguns exemplos importantes dos últimos 20 anos. Química Nova, v. 45, n. 4, p. 435-454, 2022-06-08. (18/00187-7)

HILARIO, FELIPE; POLINARIO, GIULIA; DE AMORIM, MARCELO RODRIGUES; BATISTA, VICTOR DE SOUSA; DO NASCIMENTO JUNIOR, NAILTON MONTEIRO; ARAUJO, ANGELA REGINA; BAUAB, TAIS MARIA; DOS SANTOS, LOURDES CAMPANER. Spirocyclic lactams and curvulinic acid derivatives from the endophytic fungus Curvularia lunata and their antibacterial and antifungal activities. Fitoterapia, v. 141, MAR 2020. (13/25432-0, 15/04899-3, 18/00187-7)

PIROLLA, NATALIA F. F.; BATISTA, VICTOR S.; DIAS VIEGAS, FLAVIA PEREIRA; GONTIJO, VANESSA SILVA; MCCARTHY, CAITLIN R.; VIEGAS JR, CLAUDIO; NASCIMENTO-JUNIOR, NAILTON M.. Alzheimer's Disease: Related Targets, Synthesis of Available Drugs, Bioactive Compounds Under Development and Promising Results Obtained from Multi-target Approaches. CURRENT DRUG TARGETS, v. 22, n. 5, p. 505-538, 2021. (18/00187-7)