Biomedical Engineering Reference
In-Depth Information
In (9),
I
1
is an indicator parameter defined for the presence of halogen in R
1
(
I
1
¼
1) and zero otherwise. Its positive regression coefficient suggested the favor-
able contribution of halogens when present as part of R
1
group. In (11), the
indicator variable
I
2
represents an R
2
-substituent containing COOEt moiety. Its
negative coefficient suggested that an R
2
-substituent with a specific COOEt moiety
is detrimental to the activity. These equations have suggested importance of the
steric factors in modulating the activity of these compounds [
49
].
2.3 Benzothiazine Derivatives
Benzothiazine skeleton is closely related to benzopyran scaffold. Several 1,
4-benzothiazine derivatives (8) were reported to show K
ATP
-channel opening activity
[
50
]. In 8,R
2
is Br, NO
2
,CNorCF
3
and R
1
in most of the compounds is a five- or
six-membered heterocyclic moiety. The n has a value of zero to two. The K
ATP
-
channel opening activity of these derivatives was evaluated as the smooth muscle
relaxing effect evoked on endothelium-denuded aortic rings precontracted with
20 mM KCl and was expressed as pEC50. Additionally, the binding affinities
(p
K
D
values) of these derivatives were also measured in rat aortic smooth muscle
cells (RASMC) and cardiomyocytes of the rat using [
3
H]P1075 as a radioligand.
Carosati et al. have reported a 3D-QSAR study of these 1,4-benzothiazine analogues
[
51
]. The study divulged high correlation between binding data (p
K
D
) and pEC
50
values for relaxation indicating the close similarities between cardiac K
ATP
-
channels and aortic smooth muscle K
ATP
-channels.
R
1
R
2
N
S
(O)
n
8
The 3D QSAR model was developed using GRid-Independent descriptors
(GRIND) [
52
]. The molecular interaction fields (MIFs) were generated using
GRID probes namely DRY (hydrophobic), N1 (hydrogen bond donor interaction),
O (hydrogen bond acceptor interaction) and TIP (shape description). In PLS
analysis, two latent variables were found to be optimum for modeling all the
three biological responses of these compounds. The 3D-QSAR model of smooth
muscle relaxation has explained 97% variance in the activity (
r
2
¼
0.97,
Q
2
¼
0.69, SDEC
¼
0.37, SDEP
¼
1.18). Also, the models for RASMC-binding
(
r
2
0.94,
Q
2
¼
¼
0.66, SDEC
¼
0.34, SDEP
¼
0.78) and cardiomyocytes-binding
(
r
2
0.94,
Q
2
0.73) have shown equal signifi-
cance. The study has revealed that the carbonyl on the substituent at N-4, the
hydrogen bond acceptor at C-6, the five-membered ring at N-4, and the geminal
¼
¼
0.64, SDEC
¼
0.29, SDEP
¼
