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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 4, 2006
Contents
Membrane Channels as Therapeutic Targets
Executive Editor: Jean-Claude Hervé
Membrane Channels as Therapeutic Targets -
Editorial Pp. 395
Exploiting High-Throughput Ion Channel Screening Technologies
in Integrated Drug Discovery Pp. 397-406
J.M. Treherne
[Abstract]
Brain Neuronal Nicotinic Receptors as New Targets
for Drug Discovery Pp. 407-428
C. Gotti, L. Riganti, S. Vailati and F. Clementi
[Abstract]
Na+ Channel Pharmacology and Molecular Mechanisms
of Gating Pp. 429-442
K. Yamaoka, S.M. Vogel and I. Seyama
[Abstract]
L-Type Calcium Channels Pp. 443-457
D.J. Triggle
[Abstract]
Modulation of Potassium Channels as a Therapeutic
Approach Pp. 459-470
K. Lawson and N.G. McKay
[Abstract]
On the Discovery and Development of CFTR Chloride
Channel Activators Pp. 471-484
F. Becq
[Abstract]
Membrane Ion Channels and Diabetes Pp. 485-501
P. Proks and J.D. Lippiat
[Abstract]
General Articles
Recent Progress in Pharmacological and Non-Pharmacological
Treatment Options of Major Depression Pp.
503-515
T.C. Baghai, H-J. Möller and R. Rupprecht
[Abstract]
Does Angiotensin Converting Enzyme Inhibitor Protect
the Heart in Cardiac Surgery? From Laboratory to Operating
Room: Clinical Application of Experimental Study
Pp. 517-526
Y. Shimada
[Abstract]
Abstracts
[Back
to top]
Membrane Channels as Therapeutic Targets - Editorial
A significant difficulty the pharmaceutical industry has
to face up to is the initial identification and selection
of macromolecular targets upon which de novo drug
discovery programs can be initiated. A drug target needs to
answer several criteria (as known biological function(s),
robust assay systems for in vitro characterisation
and high-throughput screening) and to be specifically modified
by and accessible to small molecular weight compounds in
vivo. Membrane channels have many of these attributes
and can be viewed as suitable targets for small molecule drugs.
Membrane channels are macromolecular protein complexes embedded
in the lipid bilayer and containing aqueous central pores
allowing the passage of ions and sometimes of small molecules.
Their functions are finely tuned by a variety of modulators,
such as enzymes and G-proteins. They play critical roles in
a broad range of physiological processes, including electrical
signal transduction, chemical signalling (involving different
second messengers), transepithelial transport, regulation
of cytoplasmic or vesicular ion concentration and pH, as well
as regulation of cell volume. Channel dysfunction may lead
to a number of diseases termed channelopathies, and a number
of common diseases (e.g. epilepsy, arrhythmia or
type II diabetes) are primarily treated by drugs that modulate
ion channel activities.
A better understanding of membrane channel structures and
of channel functions has been achieved in recent years by
three main scientific advances, the patch-clamp technique,
the use of selective neurotoxins and the cloning and sequencing
of genes. They allowed to investigate the pharmacological
effects of traditional (antiarrhythmic, antiepileptic, ...)
drugs and the development of new approaches. This issue of
Current Pharmaceutical Design, the second of three parts,
for which I have the honour to be Executive Guest Editor,
addresses topical issues to some of these channels.
Despite their disease relevance, ion channels remain until
now largely under exploited as drug targets. The ability to
apply large-scale screening formats to measures of ion channel
function offers immense opportunities for drug discovery and
academic research. Several technologies now allow to screen
large numbers of compounds and natural products on ion channel
functions to find novel drugs. Application of these technologies
has vastly improved the capabilities of ion channel drug discovery
and provides an avenue to accelerate discoveries of ion channel
biology. Mark Treherne describes [1] ion channel screening
platforms now available, together with some of their inherent
advantages and limitations.
Neuronal acetylcholine ion channel receptors (nAChRs), that
exist in several subtypes resulting from a different organisation
of various subunits around the central ion channel, are involved
in a variety of functions and disorders of the central nervous
system. Cecilia Gotti et al. [2] discuss the molecular
basis of brain nAChR structural and functional diversity mainly
in pharmacological and biochemical terms, and summarise current
knowledge concerning the newly discovered drugs used to classify
the numerous receptor subtypes and to treat the brain diseases
in which nAChRs are involved.
Voltage-gated sodium channels mediate regenerative inward
currents that are responsible for the initial depolarisation
of action potentials in excitable cells. Advances in molecular
biology have led to important new insights into the molecular
structure of the sodium channel and have shed light on the
relationship between channel structure and channel function.
Kaoru Yamaoka et al. [3] present an overview of the
various toxins and drug molecules affecting the gating behaviour
of sodium channels, providing important clues on the nature
of mobile structures involved in channel gating.
Voltage-gated L-type Ca2+ channels control depolarisation-induced
Ca2+ entry in different electrically excitable
cells, including mammalian heart but play also crucial roles
in other processes, as insulin secretory response, severe
pain or ischemic stroke. David Triggle [4] discusses the mechanisms
of action of L-type Ca2+ channels blockers as well
as the limitations on their use (e.g. their little
selectivity between subtypes of the L-type channels).
Potassium channels are a diverse and ubiquitous family of
membrane proteins present in both excitable and non-excitable
cells. Members of this channel family play critical roles
in cellular signalling processes regulating neurotransmitter
release, heart rate, insulin secretion, neuronal excitability,
epithelial electrolyte transport, smooth muscle contraction,
cell volume regulation, auditory function, hormone secretion,
immune function, cell proliferation, etc. Specific modulators
have been identified for a limited number of K+
channel subtypes. Kim Lawson and Neil McKay [5] overview the
current knowledge available concerning K+ channels
as therapeutic targets.
More than 1300 different mutations in the cystic fibrosis
transmembrane conductance regulator (CFTR) cause cystic fibrosis,
a disease characterised by deficient epithelial Cl-
secretion and enhanced Na+ absorption. Frédéric
Becq [6] summarises the recent evolution of CFTR pharmacology
and particularly how high throughput screening assays have
been developed to identify novel molecules, some of them probably
constituting a reservoir of future therapeutic agents for
cystic fibrosis.
Type-2 diabetes mellitus is considered to be due to the failure
of glucose metabolism to stimulate pancreatic β-cell
electrical activity, calcium influx, and insulin secretion
via regulation of the open probability of the ATP-sensitive
K (KATP) channels. Peter Proks and Jonathan Lippiat
[7] discuss the mechanisms, specificity and clinical implications
of the pharmacological inhibition of KATP channels
by sulphonyureas and other antidiabetic drugs.
References
[1] Treherne JM. Exploiting High-Throughput Ion Channel Screening
Technologies in Integrated Drug Discovery. Curr Pharm Design
2006; 12(4): 397-406.
[2] Gotti C, Riganti L, Vailati S, Clementi F. Brain neuronal
nicotinic receptors as new targets for drug discovery. Curr
Pharm Design 2006; 12(4): 407-428.
[3] Yamaoka K, Vogel SM, Seyama I. Na channel pharmacology
and molecular mechanisms of gating. Curr Pharm Design 2006;
12(4): 429-442.
[4] Triggle DJ. L-type calcium channels. Curr Pharm Design
2006; 12(4): 443-457.
[5] Kim Lawson & Neil G. McKay. Modulation of Potassium
Channels as a Therapeutic Approach. Curr Pharm Design 2006;
12(4): 459-470.
[6] Becq F. On the discovery and development of CFTR chloride
channel activators. Curr Pharm Design 2006; 12(4): 471-484.
[7] Proks P, Lippiat JD. Membrane ion channels and diabetes.
Curr Pharm Design 2006; 12(4): 485-501.
Jean-Claude Hervé
Interactions et Communications Cellulaires
UMR CNRS 6187, PBS, 40 avenue du R. Pineau
86022 POITIERS Cédex
France
[Back to top]
Exploiting High-Throughput Ion Channel Screening
Technologies in Integrated Drug Discovery
J.M. Treherne
Ion channels are increasingly being implicated in disease.
Although existing drugs that modulate channel function currently
represent a key class of pharmaceutical agents, future ion
channel drugs could help to treat an even wider variety of
diseases. Despite their disease relevance, ion channels remain
largely under exploited as drug targets, chiefly resulting
from the absence of screening technologies that provide the
throughput and quality of data required to support medicinal
chemistry. Although some technical challenges still lie ahead,
this historic bottleneck in drug discovery is now being bypassed
by newer technologies that can be fully integrated into the
early stages of drug discovery and will allow the discovery
of novel therapeutic agents.
Sequencing the human genome has greatly added to the number
of potential drug targets but selecting suitable ion chan-nels
for drug discovery research should be based on the potential
therapeutic relevance of the channel and not just the availability
of suitable screens. Currently, ion channel drug discovery
is focused on the need to identify compounds that can provide
tractable starting points for medicinal chemistry. Advances
in laboratory automation have brought signifi-cant opportunities
to increase screening throughput for ion channel assays but
careful assay configuration to model drug-target interactions
in a physiological manner remains an essential consideration.
Ion channel screening platforms are de-scribed in this review
to provide some insight into the variety of technologies available
for screening, together with some of their inherent advantages
and limitations.
[Back to top]
Brain Neuronal Nicotinic Receptors as New Targets
for Drug Discovery
C. Gotti, L. Riganti, S. Vailati and F. Clementi
Neuronal nicotinic receptors (nAChRs) are a heterogeneous
family of ion channels differently expressed in the nervous
system where, by responding to the endogenous neurotransmitter
acetylcholine, they contribute to a wide range of brain activities
and influence a number of physiological functions.
Over recent years, the application of newly developed molecular
and cellular biological techniques has made it possible to
correlate the subunit composition of nAChRs with specific
nicotine-elicited behaviours, and refine some of the in
vivo physiological functions of nAChR subtypes. The major
new findings are the widespread expression of nAChRs, outside
the nervous system, their specific and complex organisation,
and their relevance to normal brain function. Moreover, the
combination of clinical and basic research has better defined
the involvement of nAChRs in a growing number of nerv-ous
pathologies other than degenerative diseases.
However, there are still only a limited number of nicotinic-specific
drugs and, although some nicotinic agonists have an interesting
pharmacology, their clinical use is limited by undesirable
side effects. Some selective nicotinic ligands have recently
been developed and used to explore the complexity of nAChR
subtype structure and function in the expectation that they
will become rational therapeutic alternatives in a number
of neurodegenerative, neuropsychiatric and neuro-logical disorders.
In this review, we will discuss the molecular basis of brain
nAChR structural and functional diversity mainly in pharma-cological
and biochemical terms, and summarise current knowledge concerning
the newly discovered drugs used to clas-sify the numerous
receptor subtypes and treat the brain diseases in which nAChRs
are involved.
[Back to top]
Na+ Channel Pharmacology and Molecular
Mechanisms of Gating
K. Yamaoka, S.M. Vogel and I. Seyama
Electrogenesis of efficiently propagated action potentials
requires synchronized opening of transmembrane Na+
channels possessing a sodium selectivity-filter, a high-throughput
ion-conductance pathway, and voltage-dependent gating functions.
These properties of the Na+ channel have long been
the target of molecular analysis. Several toxins and drugs,
known to selectively bind to Na+ channels, have
been used as pharmacological tools to investigate Na+channel
properties either electrophysiologically or chemically. Recent
analyses of the protein crystal structure of bacterial volt-age-dependent
K+ channels have provided important clues to the
identity of mobile structures involved in channel gating.
The new information may be applicable to Na+ channels,
and may well require a total revision of our understanding
of gating mechanisms of sodium channels. Several experiments
challenge the emerging view that channel gating by S6 transmembrane
segments is triggered by signals from voltage sensors floating
in membrane lipid. Herein, we review the various toxin and
drug molecules that affect the gating behavior of Na+
channels in this new structural framework, by characterizing
the binding sites of these toxins, and assessing the pharmacological
effects resulting from changes in the structure of the toxin
or sodium channel.
[Back to top]
L-Type Calcium Channels
D.J. Triggle
The Ca2+ channel blockers represent a successful
group of therapeutic agents directed against cardiovascular
targets, including hypertension and angina. These drugs, including
the first-generation verapamil, nifedipine and diltiazem are
directed against a subclass of voltage-gated Ca2+
channel – the L-type channel. Other subclasses of Ca2+
channel exist and are targets for new indications.
The mechanisms of actions of the L-type blockers are discussed
and the origins of their cardiovascular selectivity discussed.
Although new drugs of this class directed against hypertension
could be developed, there are both clinical and economic reasons
that argue against such development. However, there are other
possible targets to investigate where antagonists and activators
of the L-type channel may be useful: such targets include
fertility, neuronal growth, bone for-mation and epilepsy.
Limitations to these approaches are discussed.
[Back to top]
Modulation of Potassium Channels as a Therapeutic
Approach
K. Lawson and N.G. McKay
Regulation of potassium (K+) channels evokes
hyperpolarization or repolarization of the cell membrane to
prevent or reverse cell excitability and is fundamental in
the control of cellular activity throughout the range of tissue
types within the human body. Genome projects predict that
in excess of 80 K+ channel-related genes exist,
resulting in a high degree of K+ channel diversity.
In addition, dysfunction of K+ channels, as a result
of mutations of the genes for the channel proteins or alterations
in channel regulation, has been associated with the pathophysiology
of diseases. These observations support K+ channels
as therapeutic targets to regulate cellular homeostasis in
pathophysiological conditions. Molecular cloning and expression
of K+ channels offer important information in the
identification of selective compounds to provide unique tissue
management. Specific modulators have been identified for a
limited number of K+ channel subtypes. Unfortunately
the conversion of data obtained in the laboratory to success
in the clinical setting has been limited. Tissue delivery
of genes, in combination with drugs, may be an avenue enabling
specific modulation of ion channel function and improved drug
selectivity. Using specific examples (HERG, IKs, KCNQs, KCa,
Kv1.3), issues re-garding distribution, function and diversity
related to advances made in the identification of modulators
having thera-peutic potential are discussed. The scope of
this field is just emerging and the number of likely therapeutic
indications for K+ channel modulators will increase
as insight into the dynamics of expression of these channels
in various diseases grows and the issue of the required selectivity
is resolved.
[Back to top]
On the Discovery and Development of CFTR Chloride
Channel Activators
F. Becq
Chloride channels play important roles in vital cellular
signalling processes contributing to homeostasis in both excitable
and non-excitable cells. Since 1987, more than ten ion channel
genes have been identified as causing human hereditary diseases
among them the genes for the voltage–dependent chloride
channel ClC-1 (myotonia) and the cystic fibrosis transmembrane
conductance regulator (CFTR) protein (cystic fibrosis). The
CFTR gene was cloned in 1989 and its protein product
identified as an ATP-gated and phosphorylation-regulated chloride
channel during the following two years. Since then, searching
for potent and specific small molecules able to modulate normal
and mutated CFTR has become a crucial endpoint in the field
for both our understanding of the physiological role that
CFTR plays in epithelial cells and more importantly for the
development of therapeutic agents to cure cystic fibrosis
(CF). It is predicted that a pharmacological approach would
help not only to restore the defective transport activity
of mutant CFTR but also to correct the regulatory function
of CFTR. This review describes the evolution of CFTR pharmacology
and how during the last five years, high throughput screening
assays have been developed to identify novel molecules, some
of them probably constituting a reservoir of future therapeutic
agents for CF.
[Back to top]
Membrane Ion Channels and Diabetes
P. Proks and J.D. Lippiat
Type-2, or non-insulin-dependent diabetes mellitus is a serious
disease that is now widespread throughout Western society.
Glucose intolerance, or failure of glucose to stimulate insulin
secretion, is a primary factor in the manifestation of this
disease and is likely to be due to the failure of glucose
metabolism to stimulate pancreatic β-cell
electrical activity, calcium influx, and insulin secretion.
In this review we describe how ion channels regulate the electrical
behaviour of the β-cell
and how the membrane potential depolarises in response to
a rise in glucose metabolism. Central to these electrical
events is the inhibition of ATP-sensitive potassium channel
by ATP, and we summarise recent ad-vances in our understanding
of the properties of this ion channel in coupling β-cell
metabolism to electrical activity. We discuss the mechanism,
specificity, and clinical implications of the pharmacological
inhibition of KATP channels by sul-phonyureas and other antidiabetic
drugs. The roles of other ion channels in regulating electrical
activity are considered, and also their potential use as targets
for drug action in treating β-cell
disorders
[Back to top]
Recent Progress in Pharmacological and Non-Pharmacological
Treatment Options of Major Depression
T.C. Baghai, H-J. Möller and R. Rupprecht
In spite of recent progress in the pharmacotherapy of depression
major issues are still unresolved. These include the non-response
rate of approximately 30% to conventional antidepressant pharmacotherapy,
side effects of available antidepressants and the latency
of several weeks until clinical improvement. The only non-pharmacological
biological treatment options available so far which exert
more rapid antidepressant efficacy are electroconvulsive therapy
and, as an augmentation strategy, sleep deprivation.
Current pharmacological treatments aim to enhance serotonergic
and/or noradrenergic neurotransmission. In spite of emerging
knowledge, the crucial mechanisms underlying both non-pharmacological
treatments, which are responsible for antidepressant efficacy,
are not yet clear so far. In the meantime several new pharmacological
principles are under investigation with regard to their putative
antidepressant potency. These include 5-HT1A receptor agonists,
tachykinin receptor antagonists and various interventions
within the hypothalamic-pituitary-adrenal system. While there
is evidence for antidepressant properties of these new treatments
in animal studies, in case series, in open studies and to
some degree also in placebo controlled studies, no definite
proof for the antidepressant efficacy of these new pharmacological
strategies according to the requirements for evaluation of
antidepressant drugs has been furnished so far. In contrast,
for the established non-pharmacological treatment strategies
including bright light therapy the clinical efficacy has been
proven at least in subgroups of depression, but more knowledge
of the main mechanisms underlying their antidepressant efficacy
is still necessary. In addition new non-pharmacological treatments
like repetitive transcranial magnetic stimulation, magnetic
seizure therapy and Vagus nerve stimulation are currently
under development. Nevertheless, a follow-up of both the new
pharmacological strategies and non-pharmacological treatment
options is of major importance to provide even better strategies
for the clinical management of depression, which also is of
great socio-economic impact.
[Back to top]
Does Angiotensin Converting Enzyme Inhibitor Protect
the Heart in Cardiac Surgery? From Laboratory to Operating
Room: Clinical Application of Experimental Study
Y. Shimada
Animal studies have shown angiotensin converting enzyme
(ACE) inhibitors to be effective agents for myocardial protection.
They protect against lethal arrhythmias, preserve ventricular
function, improve coronary reserve (especially after ischemia/reperfusion),
and reverse myocardial hypertrophy. Human studies, on the
other hand, have shown inconsistent results.
The beneficial effects of ACE inhibitors demonstrated in
animal studies provide major advantages for cardiac surgery.
First, most cardiac surgery is performed under ischemic arrest
induced by a cardioplegic solution, and the protective effects
of ACE inhibition against reperfusion injury can reduce peri-operative
mortality and morbidity. Second, most patients who undergo
such surgery have myocardial hypertrophy due to hypertension,
pressure or volume overload mediated by valve disease, or
myocardial infarction. Ventricular hypertrophy is a strong
risk factor for sudden death, probably from arrhythmia. Regression
of the hypertrophy may prevent post-operative sudden death,
thereby allowing for long-term benefits of surgery.
In this paper, I review ACE inhibitor studies in animals
and humans and the protective mechanisms involved. I also
discuss why human studies show inconsistent results in spite
of the fact that ACE inhibition is consistently protective
in animal studies. Finally, I explore the potential clinical
applications of ACE inhibitors in cardiac surgery.
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