Biomedical Engineering Reference
In-Depth Information
13.3.3.2 Ca
v
2-Family (N-, P/Q-, and R-Type Current)
Within this family, the Ca
v
2.2-subunit (N-type current) has attracted the most attention as potential
drug target. The most efi cient inhibitors of N-type currents are peptide toxins isolated from the
venom of i sh-eating marine snails that use these toxins to paralyze their prey. The category includes
the 25-30 amino acid residue peptides
-conotoxin MVIIA (Figure 13.8),
which bind to Ca
v
2.2 with very high afi nity and selectivity. Binding of
ω
-conotoxin GVIA and
ω
-conotoxin GVIA mainly
occurs to residues located in the pore loop region of domain III, suggesting that this toxin acts as a
pore blocker of the Ca
v
2.2-subunit.
The reason for the pharmacological interest in Ca
v
2.2 is that these channels are responsible
for neurotransmitter release in neural pathways relaying pain signals to the brain. Although
ω
ω
-conotoxins are poorly suited for use as drugs because of their lack of biomembrane permeabil-
ity,
-conotoxin MVIIA (Prialt
®
) was recently approved for use in humans. Since the drug has to
be given through an intrathecal catheter to circumvent the blood-brain barrier, the clinical use of
ω
ω
-conotoxin MVIIA is limited to severe pain in patients suffering from terminal cancer or AIDS.
A selective, nonpeptide Ca
v
2.2 blockers that can be administered orally has so far not been identi-
i ed, despite signii cant efforts, and i nding the “dihydropyridines of Cav2.2 calcium channels”
therefore still remains an open challenge!
Ca
v
2.1 channels (P/Q-type current) are generally involved in neurotransmitter release in most
synapses throughout the brain. Ca
v
2.1 can be selectively blocked by peptide toxins from either
Conus
snails (
-agatoxin IVA) (Table 13.2). From a
drug discovery point of view, however, these Ca
v
s are not of great interest, since their widespread
role in neurotransmitter release predicts severe toxicity as a consequence of channel inhibition.
The function(s) and pharmacology of Ca
v
2.3 channels (R-type current) are not well understood.
A peptide toxin, SNX-482, isolated from tarantula venom, has been found to act as a selective
blocker of Ca
v
2.3-channels.
ω
-conotoxin MVIIC) or from spider venom (
ω
13.3.3.3 Ca
v
3-Family (T-Type Current)
Certain small-molecule compounds appear to act as moderately selective blockers of Ca
v
3. The
vasodilating compound mibefradil (Figure 13.8), which has been used widely for treatment of
hypertension and angina pectoris, inhibits Ca
v
3.1-Ca
v
3.3 channels in a use-dependent way with
~10 -fold selectivity over Ca
v
1.2 channels. Moreover, certain novel dihydropyridine compounds
(e.g., R-(−)-efonidipine, Figure 13.8) inhibit Ca
v
3 channels up to ~100-fold more potently com-
pared to Ca
v
1 channels. It is not yet known exactly how these compounds interact with Ca
v
3, but
this family of ion channels seems to have a great potential as drug targets for treatment of cardio-
vascular disease. Certain classical antiepileptic compounds, such as ethosuximide, phenytoin,
and zonisamide exert their antiepileptic action at least partly via inhibition of Ca
v
3 channels.
Substances such as nickel ions (Ni
2+
),
n
-octanol, and the diuretic amiloride display moderate
selectivity for Ca
v
3 channels over the other Ca
v
channel types. Kurtoxin is a scorpion venom
toxin, which produces potent and selective blockade of Ca
v
s containing Cav3.1- and Ca
v
3.2- but
not Ca
v
3.3-subunits.
13.3.3.4 Auxiliary Subunits
The drugs gabapentin and the more recently developed pregabalin are used clinically for the treat-
ment of epilepsy and neuropathic pain. Their mechanism of action was not understood before the
discovery that gabapentin binds with extremely high afi nity to the
-subunit of Ca
v
s. Functionally,
gabapentin and pregabalin decrease the amplitude of calcium currents partially without producing
the complete blockade seen with Ca
v
inhibitors targeting the
α
2
δ
α
1
-subunit. Both Ca
v
2.1 and Ca
v
2.2 are
involved in mediating the effects of gabapentin/pregabalin. Both drugs are nontoxic, which may be
related to their partial blocking effect.
