Biomedical Engineering Reference
In-Depth Information
which produces nonselective inhibition of all type of Ca
v
s. The mechanism behind this effect is that
Cd
2+
binds to the ring of four glutamates in the selectivity i lter of the pore with much higher afi n-
ity than Ca
2+
itself and thus blocks the pore. Most of the peptide toxins, which block Ca
v
-subtypes
with high specii city, also act by producing pore block. Allosteric modulation, on the other hand,
is exemplii ed by the dihydropyridines, which selectively affect members of the Ca
v
1-family. The
binding site for these compounds is located away from the pore and their mechanism of action relies
on modii cation of the gating characteristics of the channel.
13.3.3.1 Ca
v
1-Family (L-Type Currents)
The best characterized group of Ca
v
modulators is the so-called organic calcium blockers or calcium
antagonists, comprising phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), and
the dihydropyridines (e.g., nifedipine; Figure 13.8). Several dihydropyridines are widely used clini-
cally for the treatment of cardiovascular disorders such as hypertension, angina pectoris, and cardiac
arrhythmia.
The organic calcium blockers bind with high afi nity and selectivity to
α
1
-subunits of the
Ca
v
1-family, and act as allosteric modulators. This is highlighted by the fact that among the
O
O
S
N
O
O
CN
O
N
O
O
O
Verapamil (Ca
v
1)
N
Diltiazem (Ca
v
1)
NO
2
CF
3
O
O
O
NO
2
H
3
C
NO
2
O
O
O
O
O
O
CH
3
H
H
3
C
H
P
N
O
O
Nifedipine (Ca
v
1)
Bay K 8644 (Ca
v
1)
H
Efonidipine (Ca
v
3)
O
O
O
N
N
F
CKGKGAKCSRLMYDCCTGSCRSGKC
N
ω-Conotoxin MVIIA (ziconotide/Prialt
®
) (Ca
v
2.1)
Mibefradil (Ca
v
3)
FIGURE 13.8
Chemical structure of drugs acting as blockers of Ca
v
1 (L-type) and Ca
v
3 (T-type) channels
and the amino acid sequence of the highly specii c peptide blocker of Ca
v
2.2 (N-type) channels, ω-conotoxin
MVIIA.