Biomedical Engineering Reference
In-Depth Information
Ca
2+
Ca
2+
K
+
ATP
Glucose
Antidiabetics
FIGURE 13.5
Ion channels in pancreatic β-cells and insulin secretion. The K channel subtype is called K
ATP
and it is composed of the two molecular subunits K
ir
6.2 and SUR1.
O
O
O
O
COOH
O
O
O
H
S
O
H
H
S
N
H
H
Cl
H
H
O
Glibenclamide
Tolbutamide
Metiglinide
O
N
O
N
O
NH
2
OH
H
N
N
N
O
S
Cl
F
O
O
Cromakalim
Diazoxide
Retigabine
O
N
OH
N
S
O
O
O
O
O
N
S
O
O
H
S
H
N
N
XE-991
Dofetilide
D
-Sotalol
FIGURE 13.6
Structures of the K
ATP
channel blockers glibenclamide, tolbutamide, and metiglinide; the
K
ATP
channel openers cromakalim and diazoxide; the K
V
7 channel opener retigabine; the K
V
7 channel blocker
XE-991; the K
V
11 channel blockers dofetilide and d-sotalol.
binds to this site only, whereas glibenclamide and metiglinide (Figure 13.6) binds to this as well as
to a neighboring benzamido site. The latter low-afi nity site is shared with the cardiac and vascular
subunits SUR2A and SUR2B, respectively.
The cardiovascular side effects of the SUR-blockers are minimal whereas SUR-activators, such
as cromakalim and diazoxide, which have been attempted primarily for the treatment of arterial
hypertension had to be abandoned since they cause orthostatic hypotension and rel ex tachycardia.
The K
v
channels fall into 12 subfamilies, which are all gated by changes in the membrane poten-
tial, but they exhibit different kinetics. K
v
channels can be composed of four different subunits from
the same subfamily giving numerous possibilities for variations. Several K
v
channel subfamilies are
interesting drug targets. Retigabine is an activator of the K
v
7.2/3 heteromultimeric channel being
developed for the treatment of epilepsy, and XE-991 is a memory enhancing compound blocking
the same channel (Figure 13.6).
