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.
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