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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 18, 2006
Contents
Ion Channels as a Target for Drug Design
Executive Editor: Kwok-Keung Tai
Editorial Pp. 2187
The Role of T-type Calcium Channels in Epilepsy and Pain Pp.
2189-2197
M.T. Nelson, S.M. Todorovic and E. Perez-Reyes
[Abstract]
K+ Channel Blockers: Novel Tools to Inhibit
T Cell Activation Leading to Specific Immunosuppression
Pp. 2199-2220
G. Panyi, L.D. Possani, R.C. Rodríguez de la Vega,
R. Gáspár and Z. Varga
[Abstract]
The Renal Epithelial Sodium Channel: Genetic Heterogeneity
and Implications for the Treatment of High Blood Pressure
Pp. 2221-2234
G.A. Sagnella and P.A. Swift
[Abstract]
CFTR Chloride Channel Drug Discovery – Inhibitors as
Antidiarrheals and Activators for Therapy of Cystic Fibrosis
Pp. 2235-2247
A.S. Verkman, G.L. Lukacs and L.J.V. Galietta
[Abstract]
The Voltage-Dependent Anion Channel (VDAC): Function
in Intracellular Signalling, Cell Life and Cell Death
Pp. 2249-2270
V. Shoshan-Barmatz, A. Israelson, D. Brdiczka and S.S. Sheu
[Abstract]
The Cardiac hERG/IKr
Potassium Channel as Pharmacological Target: Structure, Function,
Regulation, and Clinical Applications Pp. 2271-2283
D. Thomas, C.A. Karle and J. Kiehn
[Abstract]
The Impact of Ancillary Subunits on Small-Molecule
Interactions with Voltage-Gated Potassium Channels Pp.
2285-2302
G. Panaghie and G.W. Abbott
[Abstract]
General Articles
Molecularly Guided Therapy of Neuroblastoma: A Review
of Different Approaches Pp. 2303-2317
G.P. Tonini and V. Pistoia
[Abstract]
Endocannabinoids: A New Family of Lipid Mediators Involved
in the Regulation of Neural Cell Development Pp.
2319-2325
I. Galve-Roperh, T. Aguado, D. Rueda, G. Velasco
and M. Guzmán
[Abstract]
Abstracts
[Back
to top]
Editorial
Ion Channels as a Target for Drug Design
Ion channels play a pivotal role in transmembrane cell signaling.
Their involvement in a variety of physiological functions
and in diseases means that they are an important target for
therapeutic intervention. This issue of Current Pharmaceutical
Design is dedicated to the topic “Ion Channels as a
Target for Drug Design”.
In the first article, Nelson et al. [1] review low-voltage
activated, or T-type calcium channels in synaptic integration
and in nociception. These T-type calcium channels are potential
targets for the therapy of epilepsy and pain.
In the second article, Panyi et al. [2] discuss the
role of Kv1.3 and calcium-activated potassium channels (IKCa1)
in T cell activation and the development of their inhibitors.
Such inhibitors have therapeutic potential for a number of
diseases that involve T cell activation such as multiple sclerosis
and type I diabetes mellitus.
In the third article, Sagnella and Swift [3] review a renal
epithelial sodium channel and its role in hypertension, one
of the main causes of mortality in industrialized nations.
In the fourth article, Verkman et al. [4] describe
the identification of small molecule inhibitors of cystic
fibrosis transmembrane conductance regulator (CFTR) and the
activators of a common mutant of CFTR causing cystic fibrosis.
These inhibitors can potentially be used for the therapy of
secretory diarrheas, while activators can be employed for
the therapy of cystic fibrosis.
In the fifth article, Shoshan-Barmatz et al. [5]
give an account on the mitochondrial voltage-dependent anion
channel (VDAC) including features of channel activity and
the role of VDAC in apoptosis.
In the sixth article, Thomas et al. [6] review the
human ether-a-go-go-related gene (hERG) potassium channels,
which carry the rapid component of the cardiac repolarization
current, and hence cardiac rhythm. This article covers many
aspects of hERG channels including some novel antiarrhythmic
strategies that involve modulating the cardiac IKr
current carried by hERG channels.
It is now known that most pore-forming α-subunits
of ion channels require some ancillary subunits in the channel
complex in order to serve specific physiological roles in
vivo. In the final article, Panaghie and Abbott [7] review
how some ancillary subunits modulate the functional attributes
and pharmacology of some voltage-gated potassium channels,
which are important in the repolarization of all excitable
cells. In particular, the impact of ancillary subunits on
the development of therapeutics targeting ion channels is
discussed.
We would like to thank all of the contributors - it is their
commitment that has made this issue possible.
References
[1] Nelson MT, Todorovic SM, Perez-Reyes E. The Role of T-type
Calcium Channels in Epilepsy and Pain. Curr Pharm Des 2006;
12(18): 2189-2197.
[2] Panyi G, Possani LD, Rodríguez de la Vega RC, Gáspár
R, Varga Z. K+ Channel Blockers: Novel Tools to
Inhibit T Cell Activation Leading to Specific Immunosuppression.
Curr Pharm Des 2006; 12(18): 2199-2220.
[3] Sagnella GA, Swift PA. The Renal Epithelial Sodium Channel:
Genetic Heterogeneity and Implications for the Treatment of
High Blood Pressure. Curr Pharm Des 2006; 12(18): 2221-2234.
[4] Verkman AS, Lukacs GL, Galietta LJV. CFTR Chloride Channel
Drug Discovery – Inhibitors as Antidiarrheals and Activators
for Therapy of Cystic Fibrosis. Curr Pharm Des 2006; 12(18):
2235-2247.
[5] Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu SS. The
Voltage-Dependent Anion Channel (VDAC): Function in Intracellular
Signalling, Cell Life and Cell Death. Curr Pharm Des 2006;
12(18): 2249-2270.
[6] Thomas D, Karle CA, Kiehn J. The Cardiac hERG/IKr
Potassium Channel as Pharmacological Target: Structure, Function,
Regulation, and Clinical Applications. Curr Pharm Des 2006;
12(18): 2271-2283.
[7] Panaghie G, Abbott GW. The Impact of Ancillary Subunits
on Small-Molecule Interactions with Voltage-Gated Potassium
Channels. Curr Pharm Des 2006; 12(18): 2285-2302.
Kwok-Keung Tai, Ph.D
Associate Director
The Parkinson’s & Movement Disorder Research Laboratory
Long Beach Memorial Medical Center
Long Beach
California, USA
[Back to top]
The Role of T-type Calcium Channels in Epilepsy
and Pain
M.T. Nelson, S.M. Todorovic and E. Perez-Reyes
T-type calcium channels open in response to
small depolarizations of the plasma membrane. The entry of
two positive charges with every calcium ion leads to a further
depolarization of the membrane, the low threshold spike, and
opening of channels that have a higher threshold. In this
manner, T-channels play an important pacemaker role in gating
the activity of Na+ and Ca2+ channels.
T-channels are preferentially expressed in dendrites, suggesting
they play important roles in synaptic integration. Pharmacological
evidence indicates that they are expressed in the receptive
fields of sensory neurons, suggesting they play a primary
role in nociception. Molecular cloning of the three T-channel
genes has allowed detailed studies on their channel properties,
pharmacology, distribution in the brain, up-regulation in
animal models of disease, and provided the tools to screen
for novel drugs. Studies on transgenic animals have provided
the proof-of-concept that T-channels are important drug targets
for the treatment of absence epilepsy and neuropathic pain.
Mutations in ion channel genes, or channelopathies, have been
found in many diseases. Similarly, T-channel gene mutations
have been found in patients with childhood absence epilepsy.
Considering the important role T-channels play in the thalamus,
it is likely that T-channel mutations also contribute to a
wider range of disorders characterized by thalamocortical
dysrhythmia.
[Back to top]
K+ Channel Blockers: Novel Tools
to Inhibit T Cell Activation Leading to Specific Immunosuppression
G. Panyi, L.D. Possani, R.C. Rodríguez de la Vega,
R. Gáspár and Z. Varga
During the last two decades since the identification and characterization
of T cell potassium channels great advances have been made
in the understanding of the role of these channels in T cell
functions, especially in antigen-induced activation. Their
limited tissue distribution and the recent discovery that
different T cell subtypes carrying out distinct immune functions
show specific expression levels of these channels have made
T cell potassium channels attractive targets for immunomodulatory
drugs. Many toxins of various animal species and a structurally
diverse array of small molecules inhibiting these channels
with varying affinity and selectivity were found and their
successful use in immunosuppression in vivo was also
demonstrated. Better understanding of the topological differences
between potassium channel pores, detailed knowledge of toxin
and small-molecule structures and the identification of the
binding sites of blocking compounds make it possible to improve
the selectivity and affinity of the lead compounds by introducing
modifications based on structural information. In this review
the basic properties and physiological roles of the voltage-gated
Kv1.3 and the Ca2+-activated IKCa1 potassium channels
are discussed along with an overview of compounds inhibiting
these channels and approaches aiming at producing more efficient
modulators of immune functions for the treatment of diseases
like sclerosis multiplex and type I diabetes.
[Back to top]
The Renal Epithelial Sodium Channel: Genetic Heterogeneity
and Implications for the Treatment of High Blood Pressure
G.A. Sagnella and P.A. Swift
The renal epithelial sodium channel (ENaC) is of fundamental
importance in the control of sodium reabsorption through the
distal nephron. ENaC is an important component in the overall
control of sodium balance, blood volume and thereby of blood
pressure. This is clearly demonstrated by rare genetic disorders
of sodium channel activity (Liddle’s Syndrome and Pseudohypoaldosteronism
type 1 associated with contrasting effects on blood pressure).
Subtle dysregulation of ENaC however may also be important
in essential hypertension – a common condition and a
major cause of cardiovascular morbidity and mortality.
The epithelial sodium channel is formed from three partly
homologous subunits. In this review we deals firstly with
current views of structural and functional features of the
renal epithelial sodium channel with particular emphasis on
mechanisms and processes involved in the control of sodium
channel activity at the biochemical and cellular levels. We
then focus on genetic aspects with reference to the significance
of genetic variation in the sodium channel genes in relation
to blood pressure. In particular, we review recent investigations
on the potential clinical significance of mutations within
the genes encoding ENaC subunits in individuals with high
blood pressure. Lastly, we also examine the potential value
of pharmacological targeting of the renal epithelial sodium
channel with the sodium channel inhibitor amiloride for the
treatment of hypertension.
[Back to top]
CFTR Chloride Channel Drug Discovery – Inhibitors
as Antidiarrheals and Activators for Therapy of Cystic Fibrosis
A.S. Verkman, G.L. Lukacs and L.J.V. Galietta
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
is a cAMP-activated chloride channel expressed in epithelia
in the lung, intestine, pancreas, testis and other tissues,
where it facilitates transepithelial fluid transport. In the
intestine CFTR provides the major route for chloride secretion
in certain diarrheas. Mutations in CFTR cause the hereditary
disease cystic fibrosis, where chronic lung infection and
deterioration in lung function cause early death. CFTR is
a well-validated targeted for development of inhibitors for
therapy of secretory diarrheas and activators for therapy
in cystic fibrosis. Our lab has identified and optimized small
molecule inhibitors of CFTR, as well as activators of ΔF508-CFTR,
the most common mutant CFTR causing cystic fibrosis. High-throughput
screening of small molecule collections utilizing a cell-based
fluorescence assay of halide transport yielded thiazolidinone
and glycine hydrazide CFTR inhibitors that block enterotoxin-mediated
secretory diarrhea in rodent models, including a class of
non-absorbable inhibitors that target the CFTR pore at its
external entrance. Benzothiophene, phenylglycine and sulfonamide
potentiators were identified that correct the defective gating
of ΔF508-CFTR chloride channels, and other small molecules
that correct its defective cellular processing. Small molecule
modulators of CFTR function may be useful in the treatment
of cystic fibrosis, secretory diarrhea and polycystic kidney
disease.
[Back to top]
The Voltage-Dependent Anion Channel (VDAC): Function
in Intracellular Signalling, Cell Life and Cell Death
V. Shoshan-Barmatz, A. Israelson, D. Brdiczka and S.S. Sheu
Research over the last decade has extended the prevailing
view of mitochondria to include functions well beyond the
critical bioenergetics role in supplying ATP. It is now recognized
that mitochondria play a crucial role in cell signaling events,
inter-organelle communication, aging, many diseases, cell
proliferation and cell death.
Apoptotic signal transmission to the mitochondria results
in the efflux of a number of potential apoptotic regulators
to the cytosol that trigger caspase activation and lead to
cell destruction. Accumulating evidence indicates that the
voltage-dependent anion channel (VDAC) is involved in this
release of proteins via the outer mitochondrial membrane.
VDAC in the outer mitochondrial membrane is in a crucial position
in the cell, forming the main interface between the mitochondrial
and the cellular metabolisms. VDAC has been recognized as
a key protein in mitochondria-mediated apoptosis since it
is the proposed target for the pro- and anti-apoptotic Bcl2-family
of proteins and due to its function in the re-lease of apoptotic
proteins located in the inter-membranal space. The diameter
of the VDAC pore is only about 2.6-3 nm, which is insufficient
for passage of a folded protein like cytochrome c.
New work suggests pore formation by homo-oligomers of VDAC
or hetero-oligomers composed of VDAC and pro-apoptotic proteins
such as Bax or Bak. This review provides insights into the
central role of VDAC in cell life and death and emphasizes
its function in the regulation of mitochondria-mediated apoptosis
and, thereby, its potential as a rational target for new therapeutics.
[Back to top]
The Cardiac hERG/IKr
Potassium Channel as Pharmacological Target: Structure, Function,
Regulation, and Clinical Applications
D. Thomas, C.A. Karle and J. Kiehn
Human ether-a-go-go-related gene (hERG) potassium channels
conduct the rapid component of the delayed rectifier potassium
current, IKr,
which is crucial for repolarization of cardiac action potentials.
Moderate hERG blockade may produce a beneficial class III
antiarrhythmic effect. In contrast, a reduction in hERG currents
due to either genetic defects or adverse drug effects can
lead to hereditary or acquired long QT syndromes characterized
by action potential prolongation, lengthening of the QT interval
on the surface ECG, and an increased risk for “torsade
de pointes” arrhythmias and sudden death. This undesirable
side effect of non-antiarrhythmic compounds has prompted the
withdrawal of several blockbuster drugs from the market. Studies
on mechanisms of hERG channel inhibition provide significant
insights into the molecular factors that determine state-,
voltage-, and use-dependency of hERG current block. In addition,
crucial properties of the high-affinity drug binding site
in hERG and its interaction with drug molecules have been
identified, providing the basis for more refined approaches
in drug design, safety pharmacology and in silico
modeling. Recently, mutations in hERG have been shown to cause
current increase and hereditary short QT syndrome with a high
risk for life-threatening arrhythmias. Finally, the discovery
of adrenergic mechanisms of hERG channel regulation as well
as the development of strategies to enhance hERG currents
and to modify intracellular hERG protein processing may provide
novel antiarrhythmic options in repolarization disorders.
In conclusion, the increasing understanding of hERG channel
function and molecular mechanisms of hERG current regulation
could improve prevention and treatment of hERG-associated
cardiac repolarization disorders.
[Back to top]
The Impact of Ancillary Subunits on Small-Molecule
Interactions with Voltage-Gated Potassium Channels
G. Panaghie and G.W. Abbott
Voltage-gated potassium channels (Kv channels) are the major
determinants of cellular repolarization in excitable cells
- they open in response to depolarization and facilitate selective
efflux of potassium ions across the plasma membrane. Because
of the importance of exquisitely timed cellular repolarization
in controlling action potential morphology and duration, Kv
channels are attractive therapeutic targets, particularly
for drugs aimed at controlling aberrant electrical excitability
such as is observed in cardiac arrhythmia and epilepsy. While
the pore-forming α
subunits of Kv channels are sufficient to form functional
channels, a host of cytoplasmic and transmembrane ancillary
subunits modulate their trafficking, function and regulation
in vivo. Here, we consider the impact of ancillary
subunits on Kv channel pharmacology, and discuss how increased
understanding of the roles of ancillary subunits in native
Kv channel complexes will lead to development of safer, more
specific and more efficacious therapeutic small molecules.
[Back to top]
Molecularly Guided Therapy of Neuroblastoma: A Review
of Different Approaches
G.P. Tonini and V. Pistoia
Neuroblastoma (NB) is the most frequent extra-cranial
solid tumor and the first cause of lethality in pre-school
age children. NB accounts for 9-10% of pediatric tumors and
affects more than ten thousand children a year. It originates
from the sympathetic nervous system and is characterized by
heterogeneous pathological and clinical presentation. Stage
4 NB represents approximately 50% of the cases and shows metastatic
dissemination at onset; its prognosis is grim, with 20% of
the patients surviving at 5 years from diagnosis in spite
of aggressive chemotherapy with autologous hematopoietic stem
cell support. Novel therapeutic strategies are urgently needed
to improve the prognosis of stage 4 NB patients. Here we review
the most promising approaches to NB treatment that have already
reached clinical testing or have proved to be successful in
preclinical models of the disease. All of these approaches
are molecularly guided, since their rational development has
benefited from the enormous amount of information on the biology
of neuroblastoma gathered through molecular biology and genetics
studies. The following topics are reviewed: MYCN
oncogene amplification as parameter for therapeutic decision,
minimal residual disease, immunotherapy, gene therapy, differentiation
and apoptotic therapy, anti-angiogenic therapy, gene expression
profiling as tool for generating novel therapeutic approaches.
Although several efforts are still needed to reach a significant
cure of patients with neuroblastoma, molecularly guided approaches
have opened new ways to neuroblastoma treatment and can represent
useful models for other cancers of either childhood or adulthood.
[Back to top]
Endocannabinoids: A New Family of Lipid Mediators Involved
in the Regulation of Neural Cell Development
I. Galve-Roperh, T. Aguado, D. Rueda, G. Velasco
and M. Guzmán
The endocannabinoids (eCBs) anandamide and 2-arachidonoylglycerol
are important retrograde messengers that inhibit neurotransmitter
release via presynaptic CB1
receptors. In addition, cannabinoids are known to modulate
the cell death/survival decision of different neural cell
types, leading to different outcomes that depend on the nature
of the target cell and its proliferative/differentiation status.
Thus, cannabinoids protect primary neurons, astrocytes and
oligodendrocytes from apoptosis, whereas transformed glial
cells are prone to apoptosis by cannabinoid challenge. Moreover,
a potential role of the eCB system in neurogenesis and neural
differentiation has been proposed. Recent research shows that
eCBs stimulate neural progenitor proliferation and inhibit
hippocampal neurogenesis in normal adult brain. Cannabinoids
inhibit cortical neuron differentiation and promote glial
differentiation. On the other hand, experiments with differentiated
neurons have shown that cannabinoids also regulate neuritogenesis,
axonal growth and synaptogenesis. These new observations support
that eCBs constitute a new family of lipid signaling cues
responsible for the regulation of neural progenitor proliferation
and differentiation, acting as instructive proliferative signals
through the CB1
receptor.
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