Molecular Modeling of a Phenyl-Amidine Class of NMDA Receptor Antagonists and the Rational Design of New Triazolyl-Amidine Derivatives

Authors

  • Paula A. Abreu,

    Corresponding author
    1. LABiEMol, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Outeiro de São João Baptista, Campus Valonguinho, Centro CEP 24210-130 Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
    2. LaMCiFar, Universidade Federal do Rio de Janeiro UFRJ-Campus Macaé, Av. São José do Barreto, Macaé CEP 27965-045 RJ, Brazil
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  • Helena C. Castro,

    1. LABiEMol, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Outeiro de São João Baptista, Campus Valonguinho, Centro CEP 24210-130 Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
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  • Roberto Paes-de-Carvalho,

    1. Laboratório de Neurobiologia Celular, Instituto de Biologia, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Carlos R. Rodrigues,

    1. ModMolQSAR, Faculdade de Farmácia, UFRJ, Av Carlos Chagas Filho, 373 Cidade Universitária, CEP 21941-599 Rio de Janeiro, RJ, Brazil
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  • Viveca Giongo,

    1. LABiEMol, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Outeiro de São João Baptista, Campus Valonguinho, Centro CEP 24210-130 Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
    2. Laboratório de Virologia Molecular, Instituto de Biologia, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Izabel C. N. P. Paixão,

    1. Laboratório de Virologia Molecular, Instituto de Biologia, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Marcos V. Santana,

    1. LABiEMol, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Outeiro de São João Baptista, Campus Valonguinho, Centro CEP 24210-130 Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil
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  • Jainne M. Ferreira,

    1. Laboratório de Neurobiologia Celular, Instituto de Biologia, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Octavia M. Caversan,

    1. Laboratório de Neurobiologia Celular, Instituto de Biologia, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Raquel A. C. Leão,

    1. Laboratório de Síntese Assimétrica, Instituto de Química, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Luana M. S. Marins,

    1. Laboratório de Síntese Assimétrica, Instituto de Química, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • André M. Henriques,

    1. Laboratório de Síntese Assimétrica, Instituto de Química, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Florence M. C. Farias,

    1. Laboratório de Síntese Assimétrica, Instituto de Química, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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  • Magaly G. Albuquerque,

    1. LabMMol, Instituto de Química, UFRJ, Cidade Universitária, Ilha do Fundao CEP 21949-900 Rio de Janeiro, RJ, Brazil
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  • Sergio Pinheiro

    Corresponding author
    1. Laboratório de Síntese Assimétrica, Instituto de Química, UFF, Outeiro de São João Baptista, Campus Valonguinho. CEP 24020-150 Niterói, RJ, Brazil
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Corresponding authors: Paula A. Abreu, abreu_pa@yahoo.com.br ; Sergio Pinheiro, spinuff@gmail.com

Abstract

Recently, many efforts have been made to develop N-methyl-d-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington’s, Parkinson’s, and Alzheimer’s diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a1q), reported as N-methyl-d-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R= 0.836), presented a satisfactory internal predictive ability (Q= 0.609) and contained the descriptors (EHOMO, Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-d-aspartic acid receptor antagonists.

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