Biomedical Engineering Reference
In-Depth Information
coefficient of
L
(length parameter) indicated that lengthy substituents would pro-
duce a negative effect on the activity. It was therefore suggested that the phenyl ring
substituents may be involved in some kind of van der Waals interactions with the
active site of the receptor with some steric restrictions due to the length. In these
equations,
I
P
and
I
O
are indicator parameters for
para
- and
ortho
-substituents of 4-
and 7- benzyloxy groups of khellinone derivatives, respectively. These indicators
were given a value of one for the presence of substituent and zero for the absence.
The regression coefficients of these indicator parameters suggested that a
para
-
substituent is favorable in 4-benzyloxy series (11a) and an
ortho
-substituent unfa-
vorable in 7-benzyloxy analogues (11b)[
46
].
For a different series of khellinone derivatives studied by Baell et al. [
61
], Saini
et al. [
63
] had derived (19) correlating Kv1.3 channel blocking activity of the
compounds with calculated hydrophobicity (
C
log
P
), calculated molar refractivity
(CMR), polarizability (Pol) and a structural indicator (
I
2
). This correlation had
suggested a clear
log 1
ð
=
EC
50
Þ¼
0
:
327
ð
2
:
078
Þ þ
1
:
700
ð
1
:
310
Þ
C
log
P
2
0
:
155
ð
0
:
138
Þ
ð
C
log
P
Þ
0
:
755
ð
0
:
431
Þ
CMR
(19)
þ
0
:
242
ð
0
:
101
Þ
Pol
1
:
705
ð
0
:
962
Þ
I
2
Q
2
n
¼
22
;
r
¼
0
:
937
;
¼
0
:
82
;
s
¼
0
:
29
;
F
¼
22
:
96
;
ð
C
log
P
Þ
o
¼
5
:
48
:
role of fundamental physicochemical parameters in modulating the activity of the
compounds. While CMR suggested steric restrictions, Pol and
C
log
P
pointed out
the positive effects of polarizability and hydrophobicity of the molecules on their
activity. However, the
C
log
P
was shown to have an optimum value of 5.48. Baell
et al. [
61
] had also made a similar observation.
2.6 Benzotriazole, Benzimidazolone and Benzanilide Derivatives
The Big Potassium channels (BK channels) typically show large conductance of
potassium ions through the cell membrane. They are calcium-activated potassium
channels [
64
]. They open in response to increase in cytosolic Ca
2+
concentration
and membrane depolarization. This leads to an increased K
+
efflux, which in turn
triggers the rapid hyperpolarization of the excitatory membranes and reduces Ca
2+
influx via voltage- dependent Ca
2+
channels. BK channels are involved in a variety
of cellular functions, which include action potential repolarization, neuronal
excitability, neurotransmitter release, hormone secretion, etc. In several pathologi-
cal conditions caused by cell hyperexcitability, such as asthma, urge incontinence
and bladder spasm, gastric hypermotility, neurological and psychiatric disorders,
BK channels offer convenient handle to manage them clinically [
65
,
66
]. In view of
