Mini-Reviews in Medicinal Chemistry, Volume 3, No. 7, 2003
Contents
Carbohydrates
Executive
Editor: Istvan Toth
Aspects of the Stability and Bioavailability
of Carbohydrates and Carbohydrate Derivatives Pp. 633-649
N.B.
Drinnan and Frank Vari
Extending Chemoselective Ligation to Sugar
Chemistry: Convergent Assembly of Bioactive Neoglycoconjugates Pp. 651-658
Francesco
Peri
The Potential of the Molecular Diversity of
Heparin and Heparan Sulfate for Drug Development Pp. 659-667
Peter
Fugedi
Back to (non)-Basics: Recent Developments in
Neutral and Charge- Balanced Glycosidase Inhibitors Pp. 669-678
Todd
A. Houston and Joanne T. Blanchfield
Recent Progress in the Design of Selectin
Inhibitors Pp. 679-687
Siri
Ram Chhabra, Aisyah S. Abdul Rahim and Barrie Kellam
Recent Progress Towards the Identification of
Inhibitors of Mycobacterial Cell Wall Polysaccharide Biosynthesis Pp. 689-702
Todd L. Lowary
Conformation of Glycopeptides Pp. 703-711
Laszlo Otvos, Jr. and Mare Cudic
Recent Trends in Carbohydrate Modeling Pp. 713-717
Jane Dannow Dyekjaer and Kjeld Rasmussen
Neuropathic
Pain: Some Clues for the Future
Executive
Editor: Ana Martinez
Neuropathic Pain: Some Clues for Future Drug
Treatments Pp. 719-727
J.E. Banos, G. Sanchez, F. Berrendero and R. Maldonado
VR1 Receptor Modulators as
Potential Drugs for Neuropathic Pain Pp. 729-748
Maria L. Lopez-Rodriguez, Alma Viso and Silvia Ortega-Gutierrez
Small Molecules Targeting the NMDA Receptor
Complex as Drugs for Neuropathic Pain Pp. 749-756
Rosa Planells-Cases, Enrique Perez-Paya, Angel Messeguer, Cristina Carreno and Antonio Ferrer-Montiel
AMPA Glutamate Receptors and Neuropathic Pain Pp. 757-763
Susana Morales-Alcelay, Laura Rubio and Ana Martinez
Cannabinoids and Neuropathic Pain Pp. 765-772
P. Goya, N. Jagerovic, L. Hernandez-Folgado and M.I. Martin
Antidepressants in Chronic Neuropathic Pain Pp. 773-784
Consalvo Mattia and Flaminia Coluzzi
Drugs From the Sea: Conotoxins as Drug Leads
for Neuropathic Pain and Other Neurological Conditions Pp. 785-787
D. Alonso, Z. Khalil, N. Satkunanthan and B.G. Livett
Abstracts
[Back to top] Aspects of the Stability and Bioavailability
of Carbohydrates and Carbohydrate Derivatives
N.B.
Drinnan and Frank Vari
Carbohydrates play
a critical role in many biological processes and disease states including
cancer, inflammation and infection. The development of carbohydrates as
therapeutics continues to gain interest, as the biological roles of these
biopolymers are further elucidated and understood. However, many carbohydrates
display poor affinity, stability and bioavailability characteristics, which has
led to a widely held view that this class of molecules make poor drugs. As
there are already a significant number of carbohydrate-based drugs presently
being employed by physicians, it is clear that some carbohydrates do make
effective drugs. Recent advances in (a) the understanding of carbohydrate
specific transport mechanisms, and (b) the development of novel carbohydrate
based bioactives which may overcome many of the previous limitations of
stability and bioavailability, suggest that carbohydrate-based compounds may
provide a rich source of new drug candidates for a variety of diseases.
[Back to top] Extending Chemoselective Ligation to Sugar
Chemistry: Convergent Assembly of Bioactive Neoglycoconjugates
Francesco
Peri
Glycoproteins and
glycolipids play central roles in human health and disease, and their mimetics
are primary candidates for drug development. Our understanding of the molecular
level of phenomena based on molecular recognition of oligosaccharides by specific
receptors has taken tremendous advantage from their chemical synthesis, which
provides homogeneous material not attainable from biosynthetic systems. This
review summarizes chemoselective approaches for the assembly of
neoglycoconjugates. The objective of these methods is to make glycoconjugate
synthesis accessible to a broader community, thus accelerating progress in
biotechnology.
[Back to top] The Potential of the Molecular Diversity of
Heparin and Heparan Sulfate for Drug Development
Peter
Fugedi
Heparin and
heparan sulfate have been shown to interact with a large number of biologically
important proteins regulating important physiological processes. Specific
oligosaccharide structures within the heterogeneous polysaccharide chains are
responsible for the binding to individual proteins. Identification of specific
protein-binding oligosaccharides provides lead compounds in pharmaceutical
development and in one case has already resulted in an approved drug. The
chemical and biosynthetic basis of the molecular diversity of heparin and
heparan sulfate, its manifestation in heparin-protein interactions, and recent
progress for drug development offered by this diversity are reviewed.
[Back to top] Back to (non)-Basics: Recent Developments in
Neutral and Charge- Balanced Glycosidase Inhibitors
Todd A. Houston and Joanne T. Blanchfield
Certain
glycosidase inhibitors possess potent antiviral, antitumour and antidiabetic
properties. Glyconic acid lactones, the earliest glycosidase inhibitors
identified, have planar anomeric carbons that mimic the transition state of
glycoside hydrolysis. Other classes include lactams, glycals, epoxides, halides
and sulfonium ions, the latter based on the natural product salacinol from an
antidiabetic herb.
[Back to top] Recent Progress in the Design of Selectin
Inhibitors
Siri
Ram Chhabra, Aisyah S. Abdul Rahim and Barrie Kellam
The selectins are
a family of cell-adhesion proteins that mediate the early stages of leukocyte
recruitment from the blood stream to sites of tissue damage through recognition
of the carbohydrate epitope sialyl Lewisx (sLex). Current
development of small molecule based inhibitors of this process and their
clinical potential to address numerous acute and chronic diseases are explored.
[Back to top] Recent Progress Towards the Identification of
Inhibitors of Mycobacterial Cell Wall Polysaccharide Biosynthesis
Mycobacterial
infections have recently attracted significant attention from international
health agencies due to the resurgence of these diseases worldwide. This review
summarizes the recent work directed towards the identification of new
anti-tuberculosis agents that act by inhibiting mycobacterial cell wall
polysaccharide biosynthesis.
[Back to top] Conformation of Glycopeptides
Laszlo
Otvos, Jr. and Mare Cudic
The presence of carbohydrate
side-chains in native glycoproteins alters a number of biochemical properties
of the peptide backbone. One of the most frequently studied questions is the
conformationmodifying effect of sugar incorporation into asparagine, serine and
threonine residues. When N-glycosylation modifies the conformation, the
resulting structures are more ordered than the peptide chain without sugar
addition. For O-glycopeptides the final conformations can be either more
ordered or less ordered. In any event, only the innermost carbohydrates make
contact with the peptide backbone. Through-space structural changes are mostly
found downstream of the O-glycosylation site. In the repeat unit of epithelial
mucin-1 protein, clustering of the carbohydrates results in an easily
observable stabilization of the poly-proline II helix.
[Back to top] Recent Trends in Carbohydrate Modeling
Jane
Dannow Dyekjaer and Kjeld Rasmussen
The exploding
activities in modeling of carbohydrates during the past few years is reviewed
with emphasis on advances in improving force fields, coupling of NMR
measurements with molecular dynamics simulations, direct calculation of
thermodynamic properties, application of quantum chemical methods on a large
scale, and web-access to modeling.
[Back to top] Neuropathic Pain: Some Clues for Future Drug
Treatments
J.E.
Banos, G. Sanchez, F. Berrendero and R. Maldonado
Neuropathic pain
is still far from being adequately dealt with. Under this name, several
clinical entities have been considered and most of them only share several
painful ailments. At present, the available treatments can only alleviate the
pain of roughly half of the patients, and their effectiveness is often limited
by the appearance of the intolerable side effects. In this review, we will
consider the pathophysiology of neuropathic pain to understand the basis of
pharmacological treatments that are currently being investigated. Some examples
of these drugs will also be considered.
[Back to top] VR1 Receptor Modulators as
Potential Drugs for Neuropathic Pain
Maria
L. Lopez-Rodriguez, Alma Viso and
Silvia Ortega-Gutierrez
The involvement of
VR1 in the endogenous pain signalling has converted this receptor
into a promising therapeutic target for the development of a new family of
potent analgesics devoid of the shortcomings of other analgesics commonly used.
The desensitisation induced after VR1 activation points to the
utility of VR1 agonists for the treatment of various nociceptive
disorders including mitigation of neuropathic pain, inhibition of neurogenic
inflammation and suppression of urinary bladder hyperreflexia, whereas VR1
antagonists have been described as valuable agents for the treatment of
inflammatory hyperalgesia and pain. Structure of the main classes of VR1
ligands developed to date, their molecular mechanisms of action and their
promising utility for the management of diverse nociceptive alterations,
specially neuropathic pain, are discussed in this review.
[Back to top] Small Molecules Targeting the NMDA Receptor
Complex as Drugs for Neuropathic Pain
Rosa
Planells-Cases, Enrique Perez-Paya, Angel Messeguer, Cristina Carreno and Antonio Ferrer-Montiel
Pain is a complex
disease that usually remains poorly treated or undertreated, especially the
neuropathic pain caused by injury to the peripheral or central nervous system.
Antagonists of the NMDA receptor complex have emerged as potential drugs for
pain management. A strong case is being raised for noncompetitive or
uncompetitive antagonists with low-to-moderate affinity and fast on/offset
kinetics as drugs with good therapeutic profiles, because of their reduced side
effects.
[Back to top] AMPA Glutamate Receptors and Neuropathic Pain
Susana
Morales-Alcelay, Laura Rubio and Ana
Martinez
Glutamate
receptors are implicated in many actions in the central nervous system, as an
excitatory amino acid, and one of the more relevant is its role in
excitotoxicity. Apart from this, it also has a role as pronociceptive agent, so
that antagonizing its actions could be of interest for developing new analgesic
agents. Furthermore, between the analgesics agents, it is of outstanding
interest the fact that there is no specific therapy against the neuropathic
pain, and glutamate receptor subunits have elicited as new potential targets
for this disturbance.
[Back to top] Cannabinoids and Neuropathic Pain
P.
Goya, N. Jagerovic, L. Hernandez-Folgado
and M.I. Martin
After a brief
overview of the endocannabinoid system (CB receptors, and endocannabinoids) and
of the cannabinergic ligands, some general issues related to cannabinoids and
pain are commented. Finally, the most important findings regarding cannabinoids
and neuropathic pain are discussed in detail.
[Back to top] Antidepressants in Chronic Neuropathic Pain
Consalvo
Mattia and Flaminia Coluzzi
This review
presents available clinical studies and new insights into mechanisms of
analgesic effect and possible new routes of administration of antidepressant
drugs. Older TCAs continue to be superior treatments. We focused on recent
findings on newer antidepressants as analgesics. Their use should be supported
by further controlled trials.
[Back to top] Drugs From the Sea: Conotoxins as Drug Leads
for Neuropathic Pain and Other Neurological Conditions
D.
Alonso, Z. Khalil, N. Satkunanthan and
B.G. Livett
The oceans are a
source of a large group of structurally unique natural products that are mainly
found in invertebrates such as sponges, tunicates, bryozoans, and molluscs. It
is interesting to note that the majority of marine compounds currently in
clinical trials or under preclinical evaluation are produced by these species
rather than as secondary metabolites by marine algae [1]. Through the combined
efforts of marine natural products chemists and pharmacologists a number of
promising compounds have been identified that are either already at advanced
stages of clinical trials such as the new anti-cancer drug marine alkaloid
ecteinascidin 743 [2], or have been selected as promising candidates for
extended preclinical evaluation [3]. This is the case for conotoxins, (Table 1)
where a number of conopeptides are currently being developed as analgesics for
the treatment of neuropathic pain.