Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 7, Number 3, September 2007
Contents
Partial Dopamine Receptor Agonists as Newer Atypical
Antipsychotics: Intrinsic Activity Appropriate for Treatment
of Schizophrenic Patients Pp. 156-165
Yuji Odagaki
[Abstract]
Antifungal Therapy Used in Central Nervous System
Fungal Infections Pp. 166-172
Zhirong Yao, Wanqing Liao and Jianying Liang
[Abstract]
Diagnostic and Pathophysiological Impact of FP-CIT
SPECT in Parkinson´s Disease Pp. 173-176
Jörg Spiegel
[Abstract]
Glycine Transporter-1 Inhibitors as Novel Therapeutic
Drugs for Schizophrenia Pp. 177-182
Kenji Hashimoto
[Abstract]
Unique Insights into the Actions of CNS Agents: Lessons
from Studies of Chlorpyrifos and Other Common Pesticides
Pp. 183-199
Rory E. Mauro and Li Zhang
[Abstract]
Synthesis and Evaluation of Schiff Bases for Anticonvulsant
and Behavioral Depressant Properties Pp. 200-204
Jainendra S. Jain, Radheshyam S. Srivastava, Navneet Aggarwal
and Reema Sinha
[Abstract]
Mitochondria as Targets for Neuronal Protection Against
Excitotoxicity: A Role for Phenolic Compounds? Pp.
205-222
Bruno A. Silva, Paulo J. Oliveira, Alberto C.P. Dias and
João O. Malva
[Abstract]
Abstracts
[Back to top]
Partial Dopamine Receptor Agonists as Newer Atypical Antipsychotics:
Intrinsic Activity Appropriate for Treatment of Schizophrenic
Patients
Yuji Odagaki
Conventional antipsychotic drugs, which have been used
for a half century to treat a range of major psychiatric disorders
like schizophrenia, are being replaced by modern “atypical
antipsychotics”. Although the term “atypical”
has been applied broadly to antipsychotic drugs marketed in
the past decade, these newer drugs are strikingly heterogeneous
in chemical, pharmacological, and clinical points of view.
Recently, much attention has been directed to partial dopamine
receptor agonists as promising atypical antipsychotics with
properties of “dopamine system stabilizers”, which
behave either as agonists or antagonists depending on the
functional state of the dopamine receptors. Aripiprazole (OPC-14597)
is the first and unique antipsychotic drug with such pharmacological
properties commercially available in US, Europe, and most
recently in Japan. In the present article, the term “atypicality”
is critically revisited, and the place of partial dopamine
receptor agonists in atypical antipsychotics is overviewed
with special reference to the intrinsic activities appropriate
for treating the schizophrenic patients with greatest efficacy
and least liability of adverse effects such as extrapyramidal
symptoms.
[Back to top]
Antifungal Therapy Used in Central Nervous System
Fungal Infections
Zhirong Yao, Wanqing Liao and Jianying Liang
Amphotericin B remains an important choice for central nervous
system (CNS) fungal infections, although its adverse effects
have limited its use, especially nephratoxicity. New formulations
of amphotericin B, new azoles and echinocandins have been
developed for clinical use in the past decade. However, high
mortality is associated with CNS fungal infections, especially
those due to filamentous fungi. Mortality risk of cerebral
mucormycosis approaches 100% although amphotericin B and neurosurgical
intervention are used. Use of voriconazole has improved prognosis
of cerebral aspergillosis. However, the mortality risk of
the disease remains 70%. The antifungal therapy of minimum
of CNS fungal infections due to yeast fungi and endemic fungi,
such as Candida spp. Cryptococcus neoformans,
Coccidioides immitis, Histo-plasma capsulatum, and
Blastomyces dermatitidis has been standardized. However,
high mortality and increase of CNS fungal infections resistant
to standard therapy is waiting for utility of new antifungal
options. The treatment of CNS fungal infections due to less
common and newly emerging fungi, such as Acremonium species,
Fusarium species, Pacilomyces species, Trichoderma
species, Trichosporon species, Zygomycetes, and Phaeohyphomectes
is challenging and no well-designed studies have been carried
out, the available data are based on case reports.
In conclusion, the prognosis of CNS fungal infections is not
good. Early diagnosis, appropriate use of antifungal agents
and management of underlying disease, in combination with
neurosurgical intervention may improve the outcome.
[Back to top]
Diagnostic and Pathophysiological Impact of FP-CIT
SPECT in Parkinson´s Disease
Jörg Spiegel
Idiopathic Parkinson´s disease (PD) is characterized
by a Lewy body-degeneration of presynaptic nigrostriatal dopaminergic
neurons. This degeneration can be visualized by nuclear medicine
methods, primarily by FP-CIT SPECT: Fluoropropyl-Carbomethoxy-Iodophenyl-Tropan
(FP-CIT), marked by radioactive 123iodine,
binds to dopamine reuptake transporters at the presynaptic
membrane of the nigral dopaminergic neuron. Due to its fast
and highly affine binding (Ki
= 3.1 nM) to dopamine transporters, FP-CIT SPECT is the most
favored nuclear medicine method to support the diagnosis of
PD. FP-CIT SPECT shows a high sensitivity concerning PD (95%-100%),
a high specificity against essential tremor (100%), but a
rather low specificity against atypical parkinsonian syndromes.
FP-CIT SPECT reflects the nigrostriatal dopaminergic function
in PD, since FP-CIT SPECT correlates significantly with the
motor part of the UPDRS (Unified Parkinson´s disease
rating scale) score. Recently we correlated the nigrostriatal
FP-CIT uptake with parkinsonian cardinal symptoms hypokinesia,
rigidity, resting tremor and postural tremor: nigrostriatal
FP-CIT uptake correlated significantly inversely with the
extent of hypokinesia and rigidity, but there was no correlation
between FP-CIT uptake versus resting or postural tremor. These
findings correspond to clinical observations that hypokinesia
and rigidity – rather than resting or postural tremor
– respond well to dopaminergic drugs. Accordingly histopathological
studies disclosed a Lewy body-degeneration not only of dopaminergic
neurons but also of serotoninergic and cholinergic nuclear
grays. Nuclear medicine examinations of further cerebral transmitter
systems – primarily of the serotoninergic and the cholinergic
system – seem to be necessary to understand the pathophysiology
of resting and postural tremor in PD.
[Back to top]
Glycine Transporter-1 Inhibitors as Novel Therapeutic
Drugs for Schizophrenia
Kenji Hashimoto
Multiple lines of evidence suggest that hypofunction of glutamatergic
neurotransmission via N-methyl-D-aspartate (NMDA) receptors
might be implicated in the pathophysiology of schizophrenia.
The NMDA receptor hypofunction hypothesis of schizophrenia
suggests that increasing NMDA receptor function via pharmacological
manipulation could provide a potential new strategy for the
management of schizophrenia. Currently, the glycine modulatory
sites on NMDA receptors present the most attractive therapeutic
targets for the treatment of schizophrenia. One means of enhancing
NMDA receptor neurotransmission is to increase the availability
of the obligatory co-agonist glycine at modulatory sites through
the inhibition of glycine transporter-1 (GlyT-1) on glial
cells. With the aim of treating schizophrenia, a number of
pharmaceutical industries have developed novel and selective
GlyT-1 inhibitors, and recent studies have demonstrated that
the GlyT-1 inhibitor sarcosine (N-methyl glycine) could be
a potential drug. The present review considers GlyT-1 inhibitors
as novel drugs for the treatment of schizophrenia.
[Back to top]
Unique Insights into the Actions of CNS Agents: Lessons
from Studies of Chlorpyrifos and Other Common Pesticides
Rory E. Mauro and Li Zhang
The development of CNS drugs has been the most challenging
task in drug design. Only an abysmal one percent of nervous
system drugs tested in human clinical trials ever reach market.
This is largely attributable to the difficulties in both identifying
appropriate targets and in understanding the toxicology, pharmacology,
and pharmaceutical properties of therapeutic compounds. Pesticides
have not attracted much attention in the field of CNS drug
design. However, the toxicological and molecular actions of
certain pesticides, such as chlorpyrifos and pyrethroids,
have been well studied. Furthermore, recent epidemiological
data have provided important insights into the actions of
pesticides in the human brain. Therefore, in this review we
seek to examine and summarize the toxicological and molecular
actions of common pesticides, organophosphates and pyrethroids.
We will also summarize and compare the effects of common pesticides
on the neurological functions in animals and in humans. Common
pesticides have been shown to act on molecular targets such
as the serotonin receptors, brain-derived neurotrophic factor
(BDNF), and the transcription factor CREB. Likewise, pesticides
can affect multiple neurological functions, such as motor
coordination, habituation, attention, cognition, and psychomotor
development. A comprehensive review of the toxicological and
molecular roles of pesticides in the CNS might provide insights
into the actions of CNS agents.
[Back to top]
Synthesis and Evaluation of Schiff Bases for Anticonvulsant
and Behavioral Depressant Properties
Jainendra S. Jain, Radheshyam S. Srivastava, Navneet Aggarwal
and Reema Sinha
A series of Schiff bases of menthone has been synthesized
using an appropriate synthetic route and characterized using
Thin Layer Chromatography and spectral analysis. The synthesized
compounds were evaluated for anti-convulsant activity against
maximal electro shock (MES) and strychnine induced seizures
model in rats. The neurotoxicity and behavioral depressant
studies were also carried out using rotorod and tail suspension
methods. Results obtained show that, 84% of the compounds
afforded significant protection in the MES screen whereas
none of them found to be active in strychnine induced seizures.
Schiff base with napthyl amine was found to be most
active in the series showing activity in the dose of 10 mg/kg
in MES test. Majority of the compounds were found to be active
in behavioral depressant screening.
[Back to top]
Mitochondria as Targets for Neuronal Protection Against
Excitotoxicity: A Role for Phenolic Compounds?
Bruno A. Silva, Paulo J. Oliveira, Alberto C.P. Dias and
João O. Malva
Mitochondria are key players in the energetic metabolism,
providing energy for almost every cellular process, playing
also a central role in the maintenance of normal cellular
function. The brain has a high energy demand; hence neurons
are especially susceptible to disturbances in oxygen and nutrient
availability. Such disturbances, as observed in pathologies
such as ischemia/reperfusion or stroke, can represent an insult
with irreversible consequences to cell viability. Mitochondrial
dysfunction resulting from pathological events represents
a serious threat to cellular viability. Since mitochondria
are tightly related with a variety of cellular processes,
the loss of mitochondrial function frequently represents a
point of no return towards cell death. In this aspect, mitochondria
can also play an important role in the decision of cellular
fate – apoptosis versus necrosis.
The search for compounds aiming at neuroprotection through
the preservation of mitochondrial function might prove to
be a suitable therapeutic approach for the treatment of neurodegenerative
diseases. Examples of such molecules are phenolic compounds,
which can be found in natural sources such as in plant extracts.
Phenolics present in Hypericum perforatum are endowed
with strong antioxidant and neuroprotective properties. In
fact, the observed protection is suggested to be, at least
in part, mediated through mitochondria-based effects, indicating
a potential application for the use of such compounds or extracts
in neuroprotection.
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