Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 6, Number 1, March 2006
Contents
Recent Advances in Selective μ-Opioid
Ligands as Evaluated in Animal Models Pp. 1-14
D.E. Dar and A. Zangen
[Abstract]
Targeting Fatty Acid Metabolism in the Treatments
of Obesity and Disorders of CNS Cellular Energy Balance
Pp. 15-25
Leslie E. Landree, Eun-Kyoung Kim, Louise D. McCullough,
Francis P. Kuhajda and Gabriele V. Ronnett
[Abstract]
The Secretin/Pituitary Adenylate Cyclase-Activating
Polypeptide/ Vasoactive Intestinal Polypeptide Superfamily
in the Central Nervous System Pp. 27-57
J.Y.S. Chu, L.T.O. Lee, F.K.Y. Siu and B.K.C. Chow
[Abstract]
Elucidation of Glutamate Transporter Functions Using
Selective Inhibitors Pp. 59-71
K. Shimamoto and Y. Shigeri
[Abstract]
Neurosteroids in the Brain Neuron: Biosynthesis, Action
and Medicinal Impact on Neurodegenerative Disease Pp.
73-82
Kazuyoshi Tsutsui and Synthia H. Mellon
[Abstract]
Abstracts
[Back to top]
Recent Advances in Selective μ-Opioid
Ligands as Evaluated in Animal Models
D.E. Dar and A. Zangen
Almost 200 years ago, Serturner isolated morphine and discovered
it to be the active ingredient in opium. That was the beginning
of modern era research into opiate ligands. There have been
several important landmarks over the years in the opiates
field, including the discovery and cloning of opioid receptors
(such as μ,
Δ and κ
receptors), the discovery of their endogenous opioids (such
as the enkephalins, endorphins and dynorphins) and understanding
of the cascade of events that produce these peptides from
their corresponding proteinaceous precursors. Among the various
opioid agonists, selective μ-opioid
agonists display the best antinociceptive activity but also
the highest abuse liability, the Δ agonists have less
analgesic activity and the κ
agonists have strong central dysphoric effects and may only
be used as peripheral analgesics. There is, therefore, a continuous
effort on the part of both academia and pharmaceutical companies
to develop new synthetic opiate pain relievers having better
μ-receptor
selectivity and fewer side effects. Two endogenous μ-receptor
ligands have been discovered in recent years: endomorphins
1 and 2. They exhibit a high affinity for the μ-opioid
receptor and extremely high specificity for the μ
in preference to the Δ and κ
receptors. In an original approach, nonpeptidic agents were
developed based on the secondary structure of the enkephalins
and were found to share similarities with the three-dimensional
structure and receptor selectivity profile of the endomorphins.
Other approaches involved modification of known morphine analogs
or of endogenous ligands. This review focuses on selective
μ ligands
discovered or developed in the last decade. The behavioral
activity and the medicinal potential of these compounds are
discussed and some assessment is made as to what additional
investigations still need to be undertaken.
[Back to top]
Targeting Fatty Acid Metabolism in the Treatments
of Obesity and Disorders of CNS Cellular Energy Balance
Leslie E. Landree, Eun-Kyoung Kim, Louise D. McCullough,
Francis P. Kuhajda and Gabriele V. Ronnett
The regulation of cellular energy homeostasis within the
CNS is crucial not only to neuronal survival, but to the brain’s
function as an integrator of hormonal and neural inputs that
regulate many functions, such as feeding behavior. The sensing
and regulation of CNS cellular energy balance is altered in
many diseases. Recent studies have suggested that fatty acid
metabolism plays a significant role in regulating cellular
energy balance in the brain. This hypothesis is supported
by observations that the pharmacological manipulation of fatty
acid metabolism alters food intake and causes weight loss.
Fatty acid levels are determined by fatty acid synthase (FAS),
which catalyzes the de novo synthesis of long-chain
fatty acids that are stored as triglycerides during energy
surplus, and carnitine palmitoyltransferase-1 (CPT-1), the
rate-limiting enzyme for entry of long-chain acyl-CoA’s
into the mitochondria for fatty acid oxidation during energy
deficit. Most recently, it has been reported that pharmacological
manipulation of fatty acid metabolism can also alter cellular
energy balance in a stroke model, thus providing neuroprotection.
While the physiological contribution of fatty acid metabolism
is a hypothesis that awaits further testing, here, we review
studies from a number of laboratories investigating fatty
acid metabolism as a therapeutic approach for obesity and
disorders of CNS energy balance such as stroke.
[Back to top]
The Secretin/Pituitary Adenylate Cyclase-Activating
Polypeptide/ Vasoactive Intestinal Polypeptide Superfamily
in the Central Nervous System
J.Y.S. Chu, L.T.O. Lee, F.K.Y. Siu and B.K.C. Chow
The secretin/PACAP/VIP superfamily contains at least ten
brain-gut peptides, including secretin, pituitary adenylate
cyclase-activating polypeptide (PACAP), vasoactive intestinal
polypeptide (VIP), glucagon, glucagon-like peptide-1 (GLP-1),
glucagon like peptide-2 (GLP-2), gastric inhibitory polypeptide
(GIP), peptide histidine isoleucine (PHI) or peptide histidine
methionine (PHM), and growth hormone-releasing hormone (GHRH).
These peptides exhibit a wide tissue distribution in the peripheral
systems, indicating their pleiotrophic actions in the body.
Meanwhile, their functions in the central nervious system
(CNS) have also been consolidated recently. For instance,
most of these peptides have shown to serve as neurotransmitters,
neuromodulators, neurotrophic factors, and/or neurohormones
in the brain, and hence, their potential as novel CNS agents
in treating neurological disorders including Autism, Alzheimer’s
disease, Parkinson’s disease and HIV-associated neuronal
cell death were recently exploited. In this article, recent
progress in research of peptides in this family with particular
emphasis on structures, their central functions and potential
use in the treatment of neuronal diseases are reviewed.
[Back to top]
Elucidation of Glutamate Transporter Functions Using
Selective Inhibitors
K. Shimamoto and Y. Shigeri
L-Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system (CNS). Termination of glutamate
receptor activation and maintenance of low extracellular glutamate
concentrations are mainly achieved by glutamate transporters
(excitatory amino acid transporters 1-5: EAATs1-5) located
in nerve endings and surrounding glia cells. Selective and
potent inhibitors are needed to identify the physiological
roles of transporters in the regulation of synaptic transmission
or in the pathogenesis of neurological diseases. Glutamate
or aspartate analogs such as threo-β-hydroxyaspartate
(THA) and pyrrolidine dicarboxylate (PDC) derivatives have
served as important experimental tools. Pharmacologically
useful probes have emerged from modification of known inhibitors,
such as threo-β-benzyloxyaspartate
(DL-TBOA) which functions as a non-transportable blocker for
all subtypes of EAATs. Non-transportable blockers are indispensable
because, unlike substrates, they do not cause heteroexchange.
By comparing the effects of substrates and non-transportable
blockers, physiological roles of EAATs have been revealed.
In this review, we will describe the functions of EAATs elucidated
using these inhibitors. EAATs not only remove transmitter
from synaptic clefts but also actively modulate neurotransmission.
Moreover, high affinity ligands have been developed as novel
pharmacological tools. TBOA analogs possessing a bulky substituent
on their benzene ring significantly inhibited labeled glutamate
uptake, the most potent of compound being (2S, 3S)-3-{3-[4-(trifluoromethyl)benzoyl-amino]benzyloxy}aspartate
(TFB-TBOA). The pharmacological characterization of TFB-TBOA
is also presented in this review.
[Back to top]
Neurosteroids in the Brain Neuron: Biosynthesis, Action
and Medicinal Impact on Neurodegenerative Disease
Kazuyoshi Tsutsui and Synthia H. Mellon
The brain has traditionally been considered to be a target
site of peripheral steroid hormones. By contrast, new findings
over the past decade have shown that the brain itself also
has the capability of forming steroids de novo from
cholesterol, the so-called “neurosteroids”. To
understand neurosteroid action in the brain, data on the regio-
and temporal-specific synthesis of neurosteroids are needed.
Recently the Purkinje cell, a cerebellar neuron, has been
identified as a major site for neurosteroid formation in the
brain. Since this discovery, diverse actions of neurosteroids
are becoming clear. The rat Purkinje cell actively synthesizes
progesterone and 3α,5α-tetrahydroprogesterone (allopregnanolone)
de novo from cholesterol during neonatal life, when
cerebellar cortical formation occurs. Estrogen formation in
this neuron may also occur in the neonate. Both progesterone
and estradiol promote dendritic growth, spinogenesis and synaptogenesis
via each cognate nuclear receptor in Purkinje neurons. We
have used the Niemann-Pick type C (NP-C) mouse as a model
for understanding neurosteroid action in the brain. NP-C is
an autosomal recessive, childhood neurodegenerative disease
characterized by defective intracellular cholesterol trafficking,
resulting in Purkinje cell degeneration, as well as neuronal
degeneration in other regions. Brains from adult NP-C mice
contain less allopregnanolone than wild-type brain. Administration
of allopregnanolone to neonatal NP-C mice increases Purkinje
cell survival and delays neurodegeneration. Thus neurosteroid
replacement therapy appears to be useful in ameliorating progression
of the disease. Here we summarize the advances made in our
understanding of the biosynthesis and actions of neurosteroids
in the brain neuron. This review also describes medicinal
impact of neurosteroids on neurodegenerative disease.
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