Current Drug Targets Volume 2, Number 4, 2001
Contents
Working Memory in ADHD: Prefrontal/Parietal Connections Pp. 347-352
F. Levy and M. Farrow
Pharmacology of Appetite Suppression: Implication for the Treatment of Obesity Pp. 353-370
Jason C.G Halford
Gene Therapy: Optimising DNA Delivery to the Nucleus Pp. 371-399
Melanie Johnson-Saliba and David A. Jans
The Ca2+-Activated K+ Channel of Intermediate Conductance: A Molecular Target for Novel Treatments? Pp. 401-422
B.S. Jensen, D. Strøbæk, S.-P. Olesen and P. Christophersen
Raloxifene Pp. 423-425
John A. Kellen
An Approach for the Rational Design of New Antituberculosis Agents Pp. 427-437
K.F.M. Pasqualoto and E.I. Ferreira
[Back to top]and Working Memory in ADHD: Prefrontal/Parietal Connections
F. Levy and M. Farrow
Current theories of
dopaminergic and noradrenergic mechanisms, which are thought to be of
importance in the regulation of attention are reviewed. A biphasic model of
dopaminergic function is described, in which tonic dopamine exerts a
suppressive influence on subcortical dopamine systems by altering tonic/phasic
dopaminergic relationships. Noradrenergic mechanisms are of importance in
modulating sensory processing at the prefrontal cortical level. The work of
Silberstein and colleagues utilizing Steady-State Visually Evoked Potential,
during the course of an A-X Continuous Performance Task enables examination of
the spatial distribution and dynamics of electrical brain activity during the
task. The maintenance of activation in the interval between A and X provides a
measure of working memory, thought to be related to prefrontal-parietal
activation, which is facilitated by administration of methylphenidate to children
with ADHD, suggesting that working memory may be a core deficiency in children
with ADHD. While tonic dopamine activity in vental striatum/accumbens gates
inhibitory activity, dorsolateral prefrontal-parietal connections allow
maintenance of working memory required for goal completion.
[Back to top] Pharmacology of Appetite Suppression: Implication for the Treatment of Obesity
Jason C.G Halford
Given the current global
epidemic of obesity there is a demand for new anti-obesity drugs to overcome
the problem. Many pharmacological agents reduce food intake and significantly
decrease body mass when administered to animals but affect feeding behaviour in
a profoundly different way indicating the variety of biological mechanisms by
which such agents act (appetite verses non-appetite). More limited clinical
data demonstrates that some of the same drugs produce decreases in food intake
and weight loss in humans. A few of these drugs do so by modifying the
functioning of the appetite system as measured by subjective changes in
feelings of hunger and fullness (indices of satiety). These drugs that modify
the daily flux of appetite could be considered as ‘appetite suppressants’ with
clinical potential as anti-obesity agents. Drugs that can be considered
suitable candidates for appetite suppressants are agents that enhance
peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin
and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY,
Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such
as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone
leptin has become regarded as a key hormonal signal linking adipose tissue
status with a number of key central nervous system circuits (NPY, CART, CRF,
Melanocortins and possibly Orexins). This tonic system may also provide drug
targets for the control of appetite. Any changes induced by a potential
appetite suppressant should be considered in terms of the (i) psychological
experience and behavioural expression of appetite, (ii) metabolism and
peripheral physiology, and (iii) functioning of CNS neural pathways. In humans,
such modulation of appetite will involve changes in total caloric consumption,
subjective changes in feelings of hunger and fullness, preferences for specific
food items, and general macronutrient preferences. These may be expressed
behaviourally as changes in meal patterns, snacking behaviour and food choice.
Within the next 20 years it is certain that clinicians will have a new range of
anti-obesity compounds available to choose from. Such novel compounds may act
on a single component of the appetite system or target a combination of these
components detailed in this review. Such compounds used in combination with
life style changes and dietary intervention may be critical in dealing with the
rising world epidemic of obesity.
[Back to top] Gene Therapy: Optimising DNA Delivery to the Nucleus
Melanie Johnson-Saliba and David A. Jans
Gene therapy, the expression in
cells of genetic material that has therapeutic activity, holds great promise
for the treatment of a number of human diseases. A gene delivery vehicle, or
vector, that may be of viral or non-viral origin, is generally used to carry
the genetic material. Viral vectors have been developed that exclude
immunogenic genes while taking advantage of the genes responsible for
proficient integration of the viral genome into that of the host. In this way,
viral vectors improve the probability of long-term expression of the
therapeutic gene, whereas non-viral vectors, that are not as efficient at
introducing and maintaining foreign gene expression, have the advantage of
being non-pathogenic and non-immunogenic. Although thousands of patients have
been involved in clinical trials for gene therapy, using hundreds of different
protocols, true success has been limited. A major limitation of gene therapy
approaches, especially when non-viral vectors are used, is the poor efficiency
of DNA delivery to the nucleus; a crucial step to ensure ultimate expression of
the therapeutic gene product. Here we review existing gene delivery approaches
and, in particular, explore the possibility of enhancing non-viral gene
delivery to the nucleus by incorporating specific nuclear targeting sequences
in vectors, using a range of different strategies.
[Back to top] The Ca2+-Activated K+ Channel of Intermediate Conductance: A Molecular Target for Novel Treatments?
B.S. Jensen, D. Strøbæk, S.-P. Olesen and P. Christophersen
This review discusses the Ca2+-activated K+
channels of intermediate conductance (IK channels), and their historical
discovery in erythrocytes, their classical biophysical characteristics, physiological
function, molecular biology as well as their role as possible molecular targets
for pharmacological intervention in various diseases. The first described Ca2+-activated K+
channel ever - the so-called Gardós channel from human erythrocytes - is an IK
channel. The “I” denominates the intermediate conductance that distinguishes
the IK channels from the related Ca2+-
activated K+ channels of small (SK) or
large (BK) conductance. The recent cloning of the human IK channel gene (KCNN4)
enabled a detailed mapping of the expression in various tissues. IK channel
expression is found predominately in cells of the blood, in epithelia and
endothelia. An important physiological role of IK channels is to set the
membrane potential at fairly negative values and thereby to build up large
electrical gradients for the passive
transport of ions such as Cl- efflux driving water and Na+ secretion from epithelia, and Ca2+ influx controlling Tlymphocyte proliferation.
The molecular cloning of IK and
SK channels has revealed that both channels gain their Ca2+-sensitivity from tightly bound calmodulin (CaM). The IK
channel is potently blocked by the scorpion toxin charybdotoxin (ChTx) and the
antimycotic clotrimazole (CLT). CLT has been in clinical trials for the treatment
of sickle cell disease, diarrhea and ameliorates the symptoms of rheumatoid
arthritis. However, inhibition of cytochrome P450 enzymes by CLT limits its
therapeutic value, but new drug candidates are entering the stage.
It is discussed whether pharmacological
modulation of IK channels may be beneficial in sickle cell anemia, cystic
fibrosis, secretory diarrhea, craft-versus-host disease and autoimmune
diseases.
[Back to top] Raloxifene
John A. Kellen
Efforts to interfere with the
initiation and promotion of breast and other cancers by endocrine manipulation
are not new. It is of obvious benefit to cancer patients to administer
substances that combine minimal general toxicity with maximal oestrogen
inhibition. Raloxifene is a relatively recent addition to a group of compounds
loosely designated as antioestrogens, which implies their ability to antagonize
oestrogen effects via competitive binding to the various receptors. This is a
reductionist simplification, since their effect varies and ranges from
interaction with lipid transduction cascades, covalent binding to proteins and
DNA, regulation of growth factors, erbB2, mdr1 and probably p53 expression,
complexing with E-cadherin/catenin to active induction of apoptosis and many
other effects on the genome. Also, the action of most antioestrogens is not
solely antagonistic and different compounds do exert some agonistic effects in
various tissues. Apart from some “pure” antioestrogens, the benzothiophene
derivative Raloxifene has been found to combine a high degree of selective
oestrogen suppression with several other desirable characteristics, such as
reduction of bone demineralisation and antiatherogenic effects without
endometrial stimulation. It is well tolerated, has been successfully tested as
a chemopreventive agent for breast cancer in certain groups of the population
and does not prevent ovulation in women with normal menstrual cycles.
Certainly, Raloxifene is only another forerunner of upcoming “designer” oestrogen
modulators, but it represents a welcome addition to the therapeutic choices
available for the control of some menopausal problems as well as for the
prevention and treatment of breast cancer, as outlined in the following brief
review.
[Back to top] An Approach for the Rational Design of New Antituberculosis Agents
Tuberculosis (TB) kills more
youth and adults than any other infectious disease in the world today. The emergence
of new strains of Mycobacterium tuberculosis resistant to some or all current
antituberculosis drugs is a serious and crescent problem. The resistance is
often a corollary to HIV infection and drug-resistant TB is more difficult and
more expensive to treat, besides to be more likely fatal. Thus, it is still
necessary to search for new antimycobacterial agents. The identification of
novel targets need the identification of biochemical pathways specific to
mycobacteria and related organisms. Many unique metabolic processes occur
during the biosynthesis of mycobacterial cell wall components. In this report,
we examine one of these attractive targets for the rational design of new
antituberculosis agents – the mycolic acids.