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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 22, 2006
Contents
Always Around, Never the Same: Pathways of Amyloid Beta Induced
Neurodegeneration Throughout the Pathogenic Cascade of Alzheimer’s
Disease Pp. 2599-2605
J.J.M. Hoozemans, S.M. Chafekar, F. Baas, P. Eikelenboom and
W. Scheper
[Abstract]
Targeting Protein-Protein Interactions with Small
Molecules: Challenges and Perspectives for Computational Binding
Epitope Detection and Ligand Finding Pp. 2607-2625
Domingo González-Ruiz and Holger Gohlke
[Abstract]
A Chemical Genetics Approach for the Discovery
of Apoptosis Inducers: From Phenotypic Cell Based HTS Assay
and Structure Activity Relationship Studies, to Identification
of Potential Anticancer Agents and Molecular Targets Pp.
2627-2644
Sui Xiong Cai, John Drewe and Shailaja Kasibhatla
[Abstract]
Structural Modelling of the Human Drug-Metabolizing
Cytochromes P450 Pp. 2645-2652
David F.V. Lewis, Yuko Ito and Peter S. Goldfarb
[Abstract]
Recent Advances in Computational Prediction of
Drug Absorption and Permeability in Drug Discovery Pp.
2653-2667
Tingjun Hou, Junmei Wang, Wei Zhang, Wei Wang and Xiaojie
Xu
[Abstract]
Therapeutic Potential of Targeting the Endocannabinoids:
Implications for the Treatment of Obesity, Metabolic Syndrome,
Drug Abuse and Smoking Cessation Pp. 2669-2680
S.A. Tucci, J.C.G. Halford, J.A. Harrold and T.C. Kirkham
[Abstract]
Breathing Generation and Potential Pharmacotherapeutic
Approaches to Central Respiratory Disorders Pp. 2681-2693
Fernando Peña and Octavio García
[Abstract]
3,4-DGE is Important for Side Effects in Peritoneal
Dialysis What About its Role in Diabetes Pp. 2695-2702
Alberto Ortiz, Anders Wieslander, Torbjörn Linden,
Beatriz Santamaria, Ana Sanz, Pilar Justo, Maria-Dolores Sanchez-Niño,
Alberto Benito and Per Kjellstrand
[Abstract]
Protective Effect of Cyclosporin-A in Spinal Cord
Injury: An Overview Pp. 2703-2710
Antonio Ibarra and Araceli Diaz-Ruiz
[Abstract]
Levocetirizine: An Update Pp. 2711-2715
Garry M. Walsh
[Abstract]
Iodinated and Gadolinium Contrast Media in Computed
Tomography (CT) and Magnetic Resonance (MR) Stroke Imaging
Pp. 2717-2723
Max Wintermark and Jochen Fiebach
[Abstract]
Abstracts
[Back to top]
Always Around, Never the Same: Pathways of Amyloid
Beta Induced Neurodegeneration Throughout the Pathogenic Cascade
of Alzheimer’s Disease
J.J.M. Hoozemans, S.M. Chafekar, F. Baas, P. Eikelenboom
and W. Scheper
There is an increasing amount of evidence showing
the importance of intermediate aggregation species of amyloid
β (Aβ)
in the pathogenic cascade of Alzheimer’s disease (AD).
Different Aβ
assembly forms may mediate diverse toxic effects at different
stages of the disease. Mouse models for AD suggest that intraneuronal
accumulation of Aβ
oligomers might be involved in AD pathogenesis at a very early
stage of the disease. The detrimental effect of oligomeric
Aβ
on synaptic efficacy is suggested to be an early event in
the pathogenic cascade. Also early neuronal responses as activation
of the unfolded protein response are processes likely to be
associated with the increased occurrence of oligomeric or
low fibrillar Aβ
in AD pathology. In later stages of AD pathology, the fibrillarity
of Aβ
increases, concomitantly with a neuroinflammatory response,
followed by tau related neurofibrillary changes in end stage
pathology. We will review recent findings in in vitro
cell models, in vivo mouse models, and post mortem
AD brain tissue in view of the effects of different Aβ
peptide species on neurodegeneration during AD pathogenesis.
Insight into the role of different Aβ
species during AD pathogenesis is essential for the development
of disease modifying drugs and therapeutical strategies.
[Back to top]
Targeting Protein-Protein Interactions with
Small Molecules: Challenges and Perspectives for Computational
Binding Epitope Detection and Ligand Finding
Domingo González-Ruiz and Holger Gohlke
A promising way to interfere with biological processes
is through the control of protein-protein interactions by
means of small molecules that modulate the formation of protein-protein
complexes. Although the feasibility of this approach has been
demonstrated in principle by recent results, many of the small-molecule
modulators known to date have not been found by rational design
approaches. In large part this is due to the challenges that
one faces in dealing with protein binding epitopes compared
to, e.g., enzyme binding pockets.
Recent advances in the understanding of the energetics and
dynamics of protein binding interfaces and methodological
developments in the field of structure-based drug design methods
may open up a way to apply rational design approaches also
for finding protein-protein interaction modulators. These
advances and developments include (I) computational approaches
to dissect binding interfaces in terms of energetic contributions
of single residues (to identify “hot spot” residues),
(II) prediction of potential binding sites from unbound protein
structures, (III) recognition of allosteric binding sites
as alternatives to directly targeting interfaces, (IV) docking
approaches that consider protein flexibility and improved
descriptions of the solvent influence on electrostatic interactions,
and (V) data-driven docking approaches.
Here, we will summarize these developments with a particular
emphasis on their applicability to screen for or design small-molecule
modulators of protein-protein interactions.
[Back to top]
A Chemical Genetics Approach for the
Discovery of Apoptosis Inducers: From Phenotypic Cell Based
HTS Assay and Structure Activity Relationship Studies, to
Identification of Potential Anticancer Agents and Molecular
Targets
Sui Xiong Cai, John Drewe and Shailaja Kasibhatla
The approach of chemical genetics has been widely
used to study biological systems and to discover new drugs,
signaling pathways and targets. The current review focuses
on the development and utilization of a cell- and caspase-based
apoptosis induction assay for the discovery of apoptosis inducers.
We began with the development of a cell based phenotypic assay,
which was used for the identification of small molecules that
exhibit apoptosis inducing activities, including N-phenyl
nicotinamides, gambogic acid, indole-2-carboxylic acid benzylidene-hydrazides,
4-aryl-4H-chromenes and 3-aryl-5-aryl-1,2,4-oxadiazoles.
Through medicinal chemistry and biological studies, in
vivo active compounds were identified, such as MX116407
as a tumor vascular disrupting agent with potent in vivo
anticancer activity. The molecular targets of in vivo
active compounds were identified using reagents designed and
synthesized based on the SAR, including the identification
of tail-interacting protein 47 (TIP47), an insulin-like growth
factor II (IGF II) receptor binding protein, as the molecular
target of 3-aryl-5-aryl-1,2,4-oxadiazoles; and Transferrin
receptor I (TfR), a transmembrane protein that interacts with
transferrin (Tf) for the transport of iron into cells, as
the molecular target of gambogic acid. We demonstrated that
chemical genetics is a very useful approach for anticancer
drug research, from the discovery of potential drugs, to the
understanding of signaling pathways and identification of
druggable targets.
[Back to top]
Structural Modelling of the Human Drug-Metabolizing
Cytochromes P450
David F.V. Lewis, Yuko Ito and Peter S. Goldfarb
The structural and functional aspects of cytochrome
P450 (CYP) enzymes are reviewed in the light of current developments
in X-ray crystallography and other physical evidence, together
with recent findings on the regulation of, and polymorphisms
in, the human drug-metabolizing CYPs. It is emphasized that
the crystal structures of eukaryotic CYPs are particuarly
useful for constructing homology models of the human enzymes
associated with drug metabolism, and that these models can
aid in the high-throughput screening of novel compounds destined
for human exposure.
[Back to top]
Recent Advances in Computational Prediction
of Drug Absorption and Permeability in Drug Discovery
Tingjun Hou, Junmei Wang, Wei Zhang, Wei Wang and Xiaojie
Xu
Approximately 40%-60% of developing drugs failed
during the clinical trials because of ADME/Tox deficiencies.
Virtual screening should not be restricted to optimize binding
affinity and improve selectivity; and the pharmacokinetic
properties should also be included as important filters in
virtual screening. Here, the current development in theoretical
models to predict drug absorption-related properties, such
as intestinal absorption, Caco-2 permeability, and blood-brain
partitioning are reviewed. The important physicochemical properties
used in the prediction of drug absorption, and the relevance
of predictive models in the evaluation of passive drug absorption
are discussed. Recent developments in the prediction of drug
absorption, especially with the application of new machine
learning methods and newly developed software are also discussed.
Future directions for research are outlined.
[Back to top]
Therapeutic Potential of Targeting the Endocannabinoids:
Implications for the Treatment of Obesity, Metabolic Syndrome,
Drug Abuse and Smoking Cessation
S.A. Tucci, J.C.G. Halford, J.A. Harrold and T.C. Kirkham
Rimonabant (SR141716, Acomplia®)
has been described as an antagonist/inverse agonist at the
cannabinoid receptor type 1 (CB1). It has been
widely used as a tool to evaluate the mechanisms by which
cannabinoid agonists produce their pharmacological effects
and to elucidate the respective physiological or pathophysiological
roles of the CB1 receptor. It has become increasingly
clear that rimonabant can exert its own intrinsic actions.
These may be viewed as evidence of either the inverse agonist
nature of rimonabant or of tonic activity of the endocannabinoid
system. To date, data obtained from clinical trials (RIO North
America, RIO Europe and RIO Lipid) indicate that rimonabant
may have clinical benefits in relation to its anti-obesity
properties and as a novel candidate for the treatment of metabolic
and cardiovascular disorders associated with overweight and
obesity. Other clinical trials, such as the STRATUS study,
have also shown that rimonabant may be effective in smoking
cessation, and that the drug has a reasonable safety profile.
Recently, it has been shown that rimonabant prevents indomethacin-induced
intestinal injury by decreasing the levels of pro-inflammatory
cytokine tumour necrosis factor alpha (TNFα),
thus indicating that CB1 receptor antagonists might
exhibit potential anti-inflammatory activity in acute and
chronic diseases.
[Back to top]
Breathing Generation and Potential Pharmacotherapeutic
Approaches to Central Respiratory Disorders
Fernando Peña and Octavio García
Breathing is generated and controlled by a brainstem
neuronal network. Both intrinsic and synaptic interactions
are involved in respiratory rhythm generation and their contribution
is state-dependent, changing with hypoxia and the neuromodulatory
state. Cellular mechanisms involved in acute or chronic pathological
conditions are still unknown. A dysfunction in the neuronal
network that controls breathing may be involved in several
respiratory disorders such as central sleep apnea, sudden
infant death syndrome, congenital hypoventilation, and in
some clinical conditions that produce breathing dysfunction
such as drug-induced respiratory depression, obesity hypoventilation
syndrome, etc. Despite the fact that several drugs are currently
used to treat these diseases, the probable effects of this
pharmacotherapy on the central rhythm generator and on other
neuronal networks related with breathing control is poorly
understood. Here, we review the current pharmacological approaches
in the treatment of respiratory disorders, such as acetazolamide,
theophylline, aminophylline, progesterone, nitric oxide. Possible
effects of these drugs on the central respiratory network
are discussed and putative therapeutic targets for the development
of future pharmacological therapies suggested.
[Back to top]
3,4-DGE is Important for Side Effects in
Peritoneal Dialysis What About its Role in Diabetes
Alberto Ortiz, Anders Wieslander, Torbjörn Linden,
Beatriz Santamaria, Ana Sanz, Pilar Justo, Maria-Dolores Sanchez-Niño,
Albero Benito and Per Kjellstrand
Breakdown of glucose under physiological conditions
gives rise to glucose degradation products (GDPs). GDPs are
also formed during heat sterilization of glucose-containing
peritoneal dialysis fluids (PD-fluids). In PD-fluids GDPs
have been shown in many different in vitro assays
to be responsible for adverse effects such as growth inhibition,
and impaired leukocyte function and impaired wound healing
of peritoneal mesothelial cells. They have been linked to
changes in the peritoneal membrane as well as to the decline
in residual renal function of PD-patients. In diabetes one
of the GDPs, 3-deoxyglucosone (3-DG), has been proposed as
responsible for side-effects rather the glucose itself.
3,4-dideoxyglucosone-3-ene (3,4-DGE) was recently identified
as the most bio-reactive GDP in PD-fluids. It exists in equilibrium
with a pool of precursors, consisting of 3-DG but also of
other hitherto unidentified GDPs. In PD-fluids the concentration
of GDPs in this pool is 10–20 times as high as that
of 3,4-DGE.
In vitro 3,4-DGE induces caspase-dependent apoptosis
of neutrophils and peripheral blood mononuclear cells. Such
induction may explain immunosuppressive properties of 3,4-DGE
and contribute to an impaired peritoneal antibacterial defense.
3,4-DGE also induces renal cell apoptosis. This may explain
the better preservation of residual renal function in PD patients
not exposed to GDPs.
The concentration of 3-DG increases with worsening glycemic
control and has been implicated in the genesis of diabetic
microangiopathy. As 3,4-DGE is much more bio-reactive than
3-DG and as it may be easily recruited from the pool, it seems
probable that 3,4-DGE is the molecule involved in the diabetic
lesions rather than 3-DG itself. Thus, 3,4-DGE might contribute
to diabetic nephropathy and to the impaired antibacterial
defenses in diabetics. Unraveling of the pool dynamics of
the GDPs and the molecular mechanisms of GDP-mediated cell
injury may provide new therapeutic insights in PD and diabetes.
[Back to top]
Protective Effect of Cyclosporin-A
in Spinal Cord Injury: An Overview
Antonio Ibarra and Araceli Diaz-Ruiz
Cyclosporin-A (CsA) is a potent and selective immunosupressive
agent that, due to its mechanism of action, may be used to
inhibit both the inflammatory reaction and the synthesis of
nitric oxide (NO), a well-known neurotoxic agent. By these
means CsA may diminish overproduction of free radicals and
secondarily, lipid peroxidation (LP), both observed after
acute spinal cord (SC) injury. Studies performed on reliable
experimental models, using a well-standardized CsA dosing
scheme, showed that a low dose of this drug inhibits the expression
and activity of constitutive and inducible nitric oxide synthases
(NOS), two enzymes strongly involved in the production of
NO after SCI. Likewise, this compound inhibits LP. This inhibition
is equivalent to the one induced by methylprednisolone (MP)
at a high dose, but without the deleterious effects of the
latter upon the survival of the animals. Moreover, inhibition
of LP by CsA significantly correlates with a decrease in the
demyelination process at the epicenter of the lesion, a significant
survival of neurons in the red nucleus and enhanced motor
recovery in animals submitted to a severe SC contusion. CsA
acts as a neuroprotector agent after SC injury; hence, this
drug may be useful in the treatment of acute SCI. CsA deserves
further study in experimental animal models and in humans.
[Back to top]
Levocetirizine: An Update
Garry M. Walsh
Histamine plays a prominent and diverse role in
the pathophysiology of allergic disease and therapeutic intervention
is therefore typically focused on blocking the effects of
this biogenic amine. A new antihistamine, levocetirizine,
is the R-enantiomer of cetirizine dihydrochloride
and like its parent compound undergoes minimal hepatic metabolism.
Levocetirizine has pharmacodynamically and pharmacokinetically
favourable characteristics, including high bioavailability,
rapid onset of action, limited distribution and a low degree
of metabolism. Clinical trials indicate that it is safe and
effective for the treatment of allergic rhinitis and chronic
urticaria with a minimal number of untoward effects. Furthermore,
several recent studies have demonstrated that, in addition
to its being a potent antihistamine, levocetirizine has several
anti-inflammatory effects that are observed at clinically
relevant concentrations that may enhance its therapeutic benefit.
[Back to top]
Iodinated and Gadolinium Contrast Media
in Computed Tomography (CT) and Magnetic Resonance (MR) Stroke
Imaging
Max Wintermark and Jochen Fiebach
Thrombolysis has become an approved therapy for
acute stroke. However, many stroke patients do not benefit
from such treatment, since the presently used criteria are
very restrictive, notably with respect to the accepted time
window. Even so, a significant rate of intracranial hemorrhage
still occurs. Conventional cerebral computed tomography (CT)
without contrast has been proposed as a selection tool for
acute stroke patients. Recently, more modern magnetic resonance
imaging (MRI) and CT techniques, referred to as diffusion-
and perfusion-weighted imaging, and perfusion-CT, have been
introduced. They afford a comprehensive noninvasive survey
of acute stroke patients as soon as their emergency admission,
with accurate demonstration of the site of arterial occlusion
and its hemodynamic and pathophysiological repercussions of
the brain parenchyma. The objective of this review article
is to present the advantages and drawbacks of CT, using iodinated
contrast, and MRI, using gadolinium, in the evaluation of
acute stroke patients.
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