Structure-Activity Relationship Studies of a Series of NR2B-selective NMDA receptor Antagonists Using Molecular Modeling
Abreu, PA1,2; Albuquerque,MG1; Rodrigues, C.R.3, Pinheiro, S.4; Marins, L.M.S.4 ; Paes de Carvalho, R.5; Caversan, O.M.5 ; Castro, H.C.2
LabMMol, Instituto de Química, UFRJ 1;LABioMol, Instituto de Biologia, UFF 2;
ModMolQSAR, Faculdade de Farmácia 3; UFRJ; Instituto Química,UFF 4; Lab. de Neurobiologia, UFF5
NMDA receptor is a glutamate receptor involved in neurodegenerative chronic disorders (e.g., Alzheimer`s, Parkinson`s, Huntington`s diseases). NMDA receptor is an oligomer of NR1 subunit with one or more NR2 subunits (A-D). The subunits are differently distributed in the brain, NR2A is ubiquitously expressed in the brain whereas NR2B localization is more restricted, suggesting that agents acting selectively at this subtype may exhibit a reduced side effect profile.
In this context, we have studied the structure-activity relationships of a series of 23 amidines (1-23) from the literature that are NR2B-selective antagonist using the semiempirical AM1 method available in the SPARTAN'04 program and compared this results with those calculated for three amidines (I, II and III) synthesized by our group. The structures were optimized to a local minimum and the values of molecular volume (MV), dipole moment (DM), lipophilicity (log P), and partial charges of selected atoms were correlated to the experimental activities (pKi and pIC50). According to cross-correlation matrix, the most correlated descriptors to pKi are MV (r=0.68) and log P (r=0.68). Considering 17 compounds, pIC50 values are directly correlated with pKi values (r=0.78), excepting for compounds 1 and 2. Comparing compounds 1 to 3, they present similar log P and MV values; therefore compound 1 is able to penetrate through hydrophobic membrane but not seems to be so good antagonist as 3, probably due to the substitutent at R2 position. In another hand, in compounds 2 and 6, log P values are more than one unity different, which implies that compound 2 is not so able to permeate the membrane.
Comparing our amidines I, II and III with this series, we found some important features: high MV values (i.e., 293 ų, 348 ų and 293 ų, respectively) and medium log P values (3.78, 4.40 and 4,04 respectively), showing that these compounds should be potential antagonists of NR2B. Moreover, we proposed structural modifications of amidine I and III, including a substitutent at R1 and R2 position respectively, in order to increase the hydrophobicity.
According to these results we conclude that a more hydrophobic character associated to an enhanhecement of molecule volume can lead to more potent derivatives.
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