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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 30, 2006
Contents
Potent Adenosine A1 and A2A Receptors
Antagonists: Recent Developments Pp. 3609-3625
[Abstract]
Arginine Mimetic Structures in Biologically Active
Antagonists and Inhibitors Pp. 3627-3648
[Abstract]
Impact of Inhibitors of the Renin-Angiotensin-Aldosterone
System on Liver Fibrosis and Portal Hypertension
Pp. 3649-3661
U. Töx and H.M. Steffen
[Abstract]
Synthesis of Novel 2-(2´-Cyclopentyl)- and 2-(2´-Cyclohexyl)
Substituted 1-Naphthol Derivatives with Anticyclooxygenase
Activity Pp. 3663-3674
Ngampong Kongkathip, Komkrit Hasitapan, Narathip Pradidphol,
Kanyawim Kirtikara, Nipa Jongkon and Boonsong Kongkathip
[Abstract]
Synthesis and Biological Activity of Phosphonated
Nucleosides: Part 1. Furanose, Carbocyclic and Heterocyclic
Analogues Pp. 3675-3695
Anna Piperno, Maria A. Chiacchio, Daniela Iannazzo and
Roberto Romeo
[Abstract]
Implications of Protein Conformational Diversity
for Binding and Development of New Biological Active Compounds
Pp. 3697-3703
A.P. Valente, C.A. Miyamoto and F.C.L. Almeida
[Abstract]
An Overview of Parkinson´s Disease and the Cannabinoid
System and Possible Benefits of Cannabinoid-Based Treatments
Pp. 3705-3718
Isabel Lastres-Becker and Javier Fernández-Ruiz
[Abstract]
Serum S-100B Protein as A Biochemical Marker of Brain
Injury: A Review of Current Concepts Pp. 3719-3731
S. Korfias, G. Stranjalis, A. Papadimitriou, C. Psachoulia,
G. Daskalakis, A. Antsaklis and D.E. Sakas
[Abstract]
Abstracts
[Back to top]
Potent Adenosine A1 and A2A Receptors
Antagonists: Recent Developments
This review summarizes the current tendencies observed
in the past 5 years in the development of A1 and
A2A adenosine receptor antagonists performed in
various academia and industry. A1 and A2A
AR antagonists are as well xanthines as heteroaromatic derivatives
and are most commonly 6:5 fused heteroatomic compounds.
Among xanthine-based compounds, some common features could
be pointed out. The recent A1 AR ligands which
show good biological profile, possess long alkyl chains in
position 1 and 3 as well as bulky C(8)-substituent, while
A2A AR antagonists with a high A2A AR
affinity are C(8)-styryl substituted with N(1)-alkyl/alkynyl
moiety or fused tricyclic xanthines possessing heteroatom(s)
in the third cycle.
The research in the field of heteroaromatic A1
and A2A ARs antagonists impressively has a wide
range. Ligands are as well non-fused monocyclic substituted
compounds as fused bi- and tricyclic derivatives with the
nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine
A1 receptor non-xanthine antagonists are adenine-based,
having substituted amino group and variable nitrogen atoms
positions in the molecules. A2A AR ligands show
good affinity when furanyl function, which is crucial for
binding, is present in the fused bicyclic and tricyclic analogs.
Moreover, tricyclic nitrogen containing antagonists in order
to be active, frequently possess long-alkylphenyl moiety.
[Back to top]
Arginine Mimetic Structures in Biologically Active
Antagonists and Inhibitors
Peptidomimetics have found wide application as bioavailable,
biostable, and potent mimetics of naturally occurring biologically
active peptides. L-Arginine is a guanidino group-containing
basic amino acid, which is positively charged at neutral pH
and is involved in many important physiological and pathophysiological
processes. Many enzymes display a preference for the arginine
residue that is found in many natural substrates and in synthetic
inhibitors of many trypsin-like serine proteases, e.g.
thrombin, factor Xa, factor VIIa, trypsin, and in integrin
receptor antagonists, used to treat many blood-coagulation
disorders. Nitric oxide (NO), which is produced by oxidation
of L-arginine in an NADPH- and O2-dependent
process catalyzed by isoforms of nitric oxide synthase (NOS),
exhibits diverse roles in both normal and pathological physiologies
and has been postulated to be a contributor to the etiology
of various diseases. Development of NOS inhibitors as well
as analogs and mimetics of the natural substrate L-arginine,
is desirable for potential therapeutic use and for a better
understanding of their conformation when bound in the arginine
binding site.
The guanidino residue of arginine in many substrates, inhibitors,
and antagonists forms strong ionic interactions with the carboxylate
of an aspartic acid moiety, which provides specificity for
the basic amino acid residue in the active side. However,
a highly basic guanidino moiety incorporated in enzyme inhibitors
or receptor antagonists is often associated with low selectivity
and poor bioavailability after peroral application. Thus,
significant effort is focused on the design and preparation
of arginine mimetics that can confer selective inhibition
for specific trypsin-like serine proteases and NOS inhibitors
as well as integrin receptor antagonists and possess reduced
basicity for enhanced oral bioavailability.
This review will describe the survey of arginine mimetics
designed to mimic the function of the arginine moiety in numerous
peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors,
factor VIIa inhibitors, integrin receptor antagonists, nitric
oxide synthase inhibitors), with the aim of obtaining better
activity, selectivity and oral bioavailability.
[Back to top]
Impact of Inhibitors of the Renin-Angiotensin-Aldosterone
System on Liver Fibrosis and Portal Hypertension
U. Töx and H.M. Steffen
Morbidity and mortality of chronic liver disease are primarily
caused by liver cirrhosis and portal hypertension, both of
them secondary disorders of progressive liver fibrosis. The
main fibrogenic cell type in the liver, the hepatic stellate
cell (HSC), is activated and stimulated by several factors,
among which the renin-angiotensin-aldosterone system (RAAS)
plays a major role. Angiotensin II induces various profibrotic
pathways via the angiotensin II receptor type 1 (AT1
receptor) not only in heart and kidney, but also in liver
tissue. Stimulation of the AT1 receptor promotes
the transformation of the quiescent HSC into the myofibroblast
like activated HSC and the synthesis of transforming growth
factor-β1
(TGF-β),
the major profibrotic cytokine in the liver. In addition,
aldosterone has been suggested to induce profibrotic effects
in chronic heart and liver disease. This review focuses on
the concept that inhibitors of the RAAS retard or even reverse
liver fibrosis and reduce portal hypertension. Angiotensin
converting enzyme (ACE) inhibitors, AT1 receptor
antagonists, and aldosterone antagonists have been demonstrated
to reduce the proliferation of HSC, to decrease the synthesis
of profibrotic molecules, and to have the potential to improve
liver fibrosis. However, side-effects such as systemic hypotension
may impair the clinical application of RAAS inhibitors in
patients with liver cirrhosis and portal hypertension. Also,
efficacy may be limited by the downregulation of AT1
receptors in advanced fibrosis, which has been observed in
animal and human studies. Randomized clinical studies are
essential to evaluate, whether this approach is beneficial
in patients with chronic liver disease and progressive fibrosis.
[Back to top]
Synthesis of Novel 2-(2´-Cyclopentyl)- and 2-(2´-Cyclohexyl)
Substituted 1-Naphthol Derivatives with Anticyclooxygenase
Activity
Ngampong Kongkathip, Komkrit Hasitapan, Narathip Pradidphol,
Kanyawim Kirtikara, Nipa Jongkon and Boonsong Kongkathip
Eight novel 2-(2´-cyclopentyl)- and 2-(2´-cyclohexyl)
substituted 1-naphthol derivatives were synthesized in good
yield starting from 1-hydroxy-2-naphthoic acid. Two of them,
2-((1-(hydroxymethyl)cyclopentyl)methyl)naphthalene-1-ol (8)
and 2-((1-(hydroxymethyl)cyclohexyl)methyl)-naphthalene-1-ol
(9) showed anticyclooxygenase activity on
COX-2 with IC50 values of 19.90 μM
and 7.77 µM, respectively and 9 also
inhibited COX-1 (5.55 μM),
while the other six were inactive on both isozymes. Molecular
docking experiments indicated that the orientation of the
active naphthols is different from that of the inactive ones.
Two evidences playing important roles for the inhibition by
the active compounds, are 1) C-1 and C-3´ hydroxyl groups
formed hydrogen bonds with COX-2/COX-1 Val523/Ile523 and Arg120,
respectively, 2) hydrogen at C-5 of the naphthalene nucleus
was attracted rather close to the phenolic group of Tyr385
due to van der Waals interaction.
[Back to top]
Synthesis and Biological Activity of Phosphonated
Nucleosides: Part 1. Furanose, Carbocyclic and Heterocyclic
Analogues
Anna Piperno, Maria A. Chiacchio, Daniela Iannazzo and
Roberto Romeo
Phosphonated nucleosides represent a promising alternative
in the improvement of the biological activity of nucleoside
analogues in antiviral and anticancer chemotherapy. The basic
concept, the chemistry, the different structural modifications
and their effects on the antiviral potency will be discussed
in this review.
[Back to top]
Implications of Protein Conformational Diversity
for Binding and Development of New Biological Active Compounds
A.P. Valente, C.A. Miyamoto and F.C.L. Almeida
The new generation of biologically active compounds developed
during the 20th century relied on knowledge of enzymology
and protein structure, and were based initially, on the understanding
that protein-protein and small molecule-protein interactions
occurred through a lock-and-key mechanism. Later, evidence
suggested that this mechanism was usually followed by a conformational
change, known as induced fit. Recent studies on protein dynamics,
mainly by nuclear magnetic resonance (NMR) relaxation measurements,
have shown that proteins are not structured in a unique conformation.
Rather, they frequently have regions of conformational diversity.
In the present review we will discuss a novel view of binding,
put forward in by several research groups in the last 5 to
10 years. In the free state, protein regions displaying conformational
diversity exhibit equilibria among pre-existing conformations.
In the presence of a ligand, one of these conformations is
stabilized, so that the ligand does not need to induce a new
conformation. Upon ligand binding there is a population shift
toward the bound conformational state. Conformational diversity
of binding sites of several proteins has been measured and
has important practical as well as thermodynamical consequences:
binding sites can be mapped without prior knowledge of the
ligand and also evolution of binding sites depends mostly
on the free state, occurring at least partially independently
of the ligand.
[Back to top]
An Overview of Parkinson´s Disease and the Cannabinoid
System and Possible Benefits of Cannabinoid-Based Treatments
Isabel Lastres-Becker and Javier Fernández-Ruiz
Parkinson’s disease (PD) is a slowly progressive neurodegenerative
disorder with a heterogeneous clinical picture and a variable
rate of progression. PD is characterized by degeneration of
the pigmented neuromelanin bearing cells of the pars compacta
of the substantia nigra that leads to a severe dopaminergic
denervation of the striatum. Current treatments for PD rely
on dopamine replacement therapy, most commonly with the dopamine
precursor levodopa. Despite the many recent advances in the
symptomatic treatment of PD, there is still no realistic prospect
for a cure. In recent years, new data support the idea of
a relevant role for the cannabinoid system in PD. As cannabinoids
have neuroprotective properties, they have been proposed as
potentially useful neuroprotective substances in PD, as well
as to alleviate some symptoms in specific circumstances (i.e.
parkinsonian tremor associated with overactivity to the subthalamic
nucleus; levodopa-induced dyskinesia). By contrast, CB1
receptor antagonists might be useful to reduce bradykinesia
in patients refractory to classic levodopa treatment. The
present article will review all data about the relationship
between PD and the cannabinoid system including: i) the usefulness
of cannabinoid-related compounds to alleviate some PD symptoms;
ii) that cannabinoid-based compounds might provide protection
against the progression of neuronal injury characteristic
of this disease; iii) the influence of cannabinoids on local
inflammatory events associated with the pathogenesis in PD.
Collectively, all these evidence support that the management
of the cannabinoid system might represent a new approach to
the treatment of PD.
[Back to top]
Serum S-100B Protein as A Biochemical Marker of Brain
Injury: A Review of Current Concepts
S. Korfias, G. Stranjalis, A. Papadimitriou, C. Psachoulia,
G. Daskalakis, A. Antsaklis and D.E. Sakas
S-100 protein, described initially by Moore, constitutes
a large family of at least 20 proteins with calcium binding
ability. It is found as homo- or hetero-dimers of two different
subunits (A and B). Types S-100AB and S-100BB are described
as S-100B protein and are shown to be highly specific for
nervous tissue. It is present in the cytosol of glial and
Schwann cells, and also in adipocytes and chondrocytes, although
in very low concentrations in the latter two. The role of
protein S-100B is not yet fully understood. It is suggested
that it has intracellular and extracellular neurotropic as
well as neurotoxic function. At nanomolar levels, S-100B stimulates
neurite outgrowth and enhances survival of neurons. However,
at micromolar levels it stimulates the expression of inflammatory
cytokines and induces apoptosis. Recently, serum S-100B protein
has been proved to be an attractive surrogate marker of primary
severe brain injury and secondary insults. It can be measured
in the arterial and venous serum; it is not affected by haemolysis
and remains stable for several hours without the need for
immediate analysis. Its short half-life makes measurements
crucial in the emergency and intensive care settings.
This review summarises published findings on S-100B regarding
its role as a serum biochemical marker of brain injury, i.e.,
after severe, moderate or mild neuro-trauma, subarachnoid
haemorrhage, thrombo-embolic stroke, cerebral ischaemia and
brain tumours, as well as extracranial trauma, neurodegenerative
and psychiatric disorders.
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