Biomedical Engineering Reference
In-Depth Information
the orientation of the individual carbonyl groups of the C-3 and C-5 ester
substituents with respect to the dihydropyridine ring double bond, three differ-
ent conformations are possible for the ester groups:
trans/trans
,
cis/cis
and
enantiomeric
cis/trans
, and
trans/cis
arrangements [
65
]. Furthermore, it has
been suggested that syn-periplanar carbonyl groups might be a common feature
of dihydropyridines calcium-channel antagonists and that an antiperiplanar
carbonyl group, such as the lactone group in the rigid compounds, might be
prerequisite for calcium-channel agonist activity [
63
].
(d) When the esters at C-3 and C-5 are different, C-4 carbon becomes chiral and
stereoselectivity between enantiomers is presented [
67
].
(e) Modified activity can be obtained by altering the changes at C-2 and C-6
substituents. The receptor can tolerate different changes [
63
,
67
].
(f) In unsymmetrical dihydropyridines, C-4 is a chiral center. It was suggested that
calcium-channel modulation (antagonist versus agonist activity) is dependent
on the absolute configuration at C-4, whereby the orientation of the 4-aryl group
(
R
versus
S
-enantiomer) acts as a “molar switch” between antagonist and
agonist activity [
40
,
55
,
68
]. The replacement of large lipophilic groups by
small ester groups presenting a negative potential (e.g., nitro group) will be the
point of chirality for the C-4. The resulting individual enantiomers will have
exactly the opposite biological response [
54
]. Instead of blocking the entry of
calcium into cardiac and vascular muscle, these derivatives will enhance it.
Thus, these derivatives are characterized as “calcium agonists” or “calcium-
channel activators” [
54
].
Coburn et al. [
45
] applied a Hansch analysis to a series of 45 4-phenyl-
substituted dihydropyridines (Fig.
2
). They concluded that the biological activity
is dependent on the lipophilic, as well as the electronic and steric properties of the
substituents on 4-phenyl dihydropyridines analogs of nifedipine [
45
].
Hemmateenejad et al. [
63
,
69
] examined the same data set, using multiple linear
regressions combined with genetic algorithm for variable selection and an artificial
neural network model combined with principal component analysis for dimension
reduction and genetic algorithm for factor selection. The resulting equations
suggested that the electronic properties of the atoms belonging to the backbone of
the molecules as well as the conformation of the molecules affect the binding
of these molecules with their receptor.
In 2008, Hemmateenejad et al. [
62
] evaluated a novel type of electronic
descriptors called quantum topological molecular similarity (QTMS) indices for
describing the quantitative effects of molecular electronic environments on the
antagonistic activity of the same dihydropyridine derivatives. QTMS theory
produces a matrix of descriptors, including bond (or structure) information in one
dimension and electronic effects in another dimension, for each molecule. The
significant effects of chemical bonds on the antagonistic activity were identified by
calculating variable important in projection (VIP). It was obtained that those
belongings to the substituted 4-phenyl ring represent high influence on the
biological activity.
