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CNS &
Neurological Disorders - Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 5, Number 3, June 2006
Contents
G Protein-Coupled Receptors as Targets for the Pharmacological
Treatment of Obesity
Guest Editor: Helgi B. Schiöth
G Protein-Coupled Receptors in Regulation of
Body Weight Pp.241-249
Helgi B. Schiöth
[Abstract]
Melanocortin Receptors as Drug Targets for Disorders
of Energy Balance Pp. 251-261
Roger A.H. Adan and Gertjan van Dijk
[Abstract]
NPY Receptors as Drug Targets for the Central
Regulation of Body Weight Pp. 263-274
Michel Félétou, Jean-Pierre Galizzi and
Nigel R. Levens
[Abstract]
Endocannabinoids in Appetite Control and the Treatment
of Obesity Pp. 275-292
T.C. Kirkham and S.A. Tucci
[Abstract]
Monoamine Receptors in the Regulation of Feeding
Behaviour and Energy Balance Pp. 293-312
P.G. Clifton and G.A. Kennett
[Abstract]
Roles of Orexins and Orexin Receptors in
Central Regulation of Feeding Behavior and Energy Homeostasis
Pp. 313-325
Takeshi Sakurai
[Abstract]
Galanin/GALP Receptors and CNS Homeostatic Processes
Pp. 327-334
J.K. Robinson, T. Bartfai and Ü. Langel
[Abstract]
Growth Hormone Secretagogue (Ghrelin-) Receptors
- A Complex Drug Target for the Regulation of Body Weight
Pp. 335-343
R. Nogueiras, D. Perez-Tilve, K.E. Wortley and M. Tschöp
[Abstract]
General Articles
D1
and Functionally Selective Dopamine Agonists as Neuroprotective
Agents in Parkinson’s Disease Pp. 345-353
M.M. Lewis, X. Huang1, D.E. Nichols and R.B. Mailman
[Abstract]
Signaling Mechanisms Underlying Aβ
Toxicity: Potential Therapeutic Targets for Alzheimer’s
Disease Pp. 355-361
Wanli W. Smith, Myriam Gorospe and John W. Kusiak
[Abstract]
The Vitamin D Neuroendocrine System as a Target
for Novel Neurotropic Drugs Pp. 363-371
A.V. Kalueff, A. Minasyan, T. Keisala, M. Kuuslahti, S.
Miettinen and P. Tuohimaa
[Abstract]
Abstracts
[Back to top]
G Protein-Coupled Receptors in Regulation of Body
Weight
Helgi B. Schiöth
In this issue of CNS & Neurological Disorders-Drug Targets,
we focus on G protein-coupled receptors (GPCRs) that are involved
in regulating body weight. In six reviews, the melanocortins
system (including MC4 and MC3 receptors, Agrp, MSH), the NPY
receptors (including NPY-Y1, NPY-Y2, and NPY-Y5, PYY3-36),
the cannabinoid system (including the development of rimonabant),
the ghrelin (GHS, growth hormone secretagogue) system, the
monoamine GPCRs (including serotonin, adrenergic and histamine
receptors), orexin (hypocretin) system and the galanin receptors
are covered. In this overview, an introduction to the GPCRs
and the field of central regulation of food intake is provided
together with brief mentioning of some other GPCRs that are
also implicated in regulation of body weight, such as the
melanin-concentrating hormone (MCH), neuromedin U, prolactin-releasing
peptide (PrRP), bombesin, cholecystokinin (CCK), Glucagon-like
peptide-1 (GLP-1) (and oxyntomodulin), neuropeptide B (NPB)
and neuropeptide W (NPW), opioids peptides, free fatty acid
(FFA) receptors (GPR40, GPR41). In total over 40 GPCRs are
listed that have been implicated to affect regulation of body
weight.
[Back to top]
Melanocortin Receptors as Drug Targets for Disorders
of Energy Balance
Roger A.H. Adan and Gertjan van Dijk
There is overwhelming evidence that the brain melanocortin
system is a key regulator of energy balance, and dysregulations
in the brain melanocortin system can lead to obesity. The
melanocortin system is one of the major down-stream leptin
signaling pathways in the brain. In contrast to leptin, preclinical
studies indicate that diet-induced obese animals are still
responsive to the anorectic effects of melanocortin receptor
agonists, suggesting the melanocortin system is an interesting
therapeutic opportunity. Besides regulating energy balance,
melanocortins are involved in a variety of other neuroendocrine
processes, including inflammation, blood pressure regulation,
addictive and sexual behavior, and sensation of pain. This
review evaluates the melanocortin system function from the
perspective to use specific melanocortin (MC) receptors as
drug targets, with a focus on the treatment of obesity and
eating disorders in humans, and the implications this may
have on mechanisms beyond the control of energy balance.
[Back to top]
NPY Receptors as Drug Targets for the Central Regulation
of Body Weight
Michel Félétou, Jean-Pierre Galizzi and
Nigel R. Levens
Neuropeptide Y (NPY) is present in the hypothalamus, where
it is believed to play a key role in the control of food intake.
Evidence for this assertion has come from studies demonstrating
that acute administration of NPY into the hypothalamus or
into the brain ventricles leads to increased food intake.
In the case of chronic administration, the hyperphagic effects
of NPY are prolonged leading to the development of an obese
state. NPY levels in the hypothalamus are temporally correlated
with food intake and are markedly elevated in response to
energy depletion. However, attempts to demonstrate an important
role for NPY in the control of food intake using NPY knockout
mice, NPY antisense oligodeoxynucleotides and anti-NPY antibodies
has produced equivocal results. Despite this many pharmaceutical
companies have moved ahead with the search for agonists and
antagonists of NPY receptor subtypes as antiobesity agents.
Antagonists of the NPY Y1
and NPY Y5
receptor subtype initially looked promising since analogs
of NPY with high selectivity for these receptors strongly
stimulated food intake. However, attempts to inhibit the signaling
of NPY through the NPY Y1
and NPY Y5
receptors has produced equivocal effects on food intake. Recent
observations that the gut derived peptide PYY3-36
suppresses appetite by stimulating both peripherally and centrally
located NPY Y2
receptors remain controversial in animals but the effects
look promising in human studies. Whether this will be the
long awaited therapy based on manipulation of NPY receptors
will await further studies of long term efficacy and more
importantly a favorable side effect profile.
[Back to top]
Endocannabinoids in Appetite Control and the Treatment
of Obesity
T.C. Kirkham and S.A. Tucci
Research into the endocannabinoid ‘system’ has
grown exponentially in recent years, with the discovery of
cannabinoid receptors and their endogenous ligands, such as
anandamide and 2-arachidonoylglycerol (2-AG). Important advances
have been made in our understanding of endocannabinoid transduction
mechanisms, their metabolic pathways, and of the biological
processes in which they are implicated. A decade of endocannabinoid
studies has promoted new insights into neural regulation and
mammalian physiology that are as revolutionary as those arising
from the discovery of the endogenous opioid peptides in the
1970s. Thus, endocannabinoids have been found to act as retrograde
signals: released by postsynaptic neurons, they bind to presynaptic
heteroceptors to modulate the release of inhibitory and excitatory
neurotransmitters through multiple G-protein-coupled receptor
(GPCR)-linked effector mechanisms. The metabolic pathways
of anandamide and 2-AG have now been been characterised in
great detail, and we can anticipate that these pathways –
together with endocannabinoid uptake mechanisms – will
complement cannabinoid receptors as targets for the pharmacological
analysis of the physiological functions of these substances.
Specific insights into the potential role of endocannabinoid-CB1
receptor systems in central appetite control, peripheral metabolism
and body weight regulation herald the clinical application
of CB1 receptor antagonists in the management of obesity and
its associated disorders.
[Back to top]
Monoamine Receptors in the Regulation of Feeding Behaviour
and Energy Balance
P.G. Clifton and G.A. Kennett
We evaluate the likely utility of drugs that interact, either
directly or indirectly, with monoamine binding receptors for
the treatment of obesity. We discuss ligands at dopaminergic,
adrenergic, serotoninergic and histaminergic receptors and
also drugs that either release or inhibit the reuptake of
monoamine neurotransmitters. We review evidence from preclinical
studies of receptor distribution and function, together with
the consequences of gene deletion in transgenic mouse strains
and the results from human studies where these are available.
In addition we consider the side effect profiles that would
be expected of these potential anti-obesity treatments. We
conclude that compounds interacting with 5-HT2C,
5-HT6
and histamine H3
receptors may be of particular interest as specific drug development
targets for the treatment of appetite disturbance in obesity.
[Back to top]
Roles of Orexins and Orexin Receptors in Central Regulation
of Feeding Behavior and Energy Homeostasis
Takeshi Sakurai
Orexins were initially recognized as regulators of feeding
behavior due to their exclusively production in the lateral
hypothalamic area (LHA), a feeding center. Subsequently, the
finding that orexin deficiency causes narcolepsy in humans
and animals suggested that these hypothalamic neuropeptides
play a critical role in regulating and maintaining sleep/wakefulness
states. Proper maintenance of arousal during food searching
and intake is essential for an animal’s survival. Therefore,
feeding behavior and sleep/wakefulness states are appropriately
coordinated. For example, when faced with reduced food availability,
animals adapt with a longer wakefulness period, which disrupts
the normal circadian pattern of activity. The discovery that
orexin neurons are regulated by peripheral metabolic cues,
including ghrelin, leptin and glucose, suggests that they
might have important roles as a link between energy homeostasis
and sleep/wakefulness states. Recent studies on afferent (input)
systems of orexin neurons further suggest roles of orexin
and orexin receptors in the coordination of feeding, arousal
and emotion.
[Back to top]
Galanin/GALP Receptors and CNS Homeostatic Processes
J.K. Robinson, T. Bartfai and Ü. Langel
Galanin is a 29/30 amino acid peptide neurotransmitter that
is widely distributed throughout the central nervous system
and periphery. There are three well-characterized G-protein
coupled galanin receptors subtypes (GalR1-3). A more recently
discovered 60 amino acid galanin-like peptide (GALP) shares
amino acid sequence homology with galanin (1-13) in position
9-21 and has high binding affinity for GalR1-3, with highest
affinity for GalR3. Considerable evidence has accumulated
that implicates both galanin and GALP as playing important
roles in regulating food and water intake behavior and related
neuroendocrine functions. Pharmacological tools are emerging
that will allow dissociation of specific roles for the peptides
and their associated receptor subtypes in mediating the homeostatic
processes of energy and fluid balance.
[Back to top]
Growth Hormone Secretagogue (Ghrelin-) Receptors -
A Complex Drug Target for the Regulation of Body Weight
R. Nogueiras, D. Perez-Tilve, K.E. Wortley and M. Tschöp
The growth hormone secretagogue receptor (GHS-R) is expressed
in several tissues and seems to mediate the different actions
of the synthetic growth hormone secretagogues (GHS) and the
endogenous ligand of this receptor, ghrelin. The GHS-R belongs
to the family of G-protein coupled receptors (GPCR). Two different
receptor variants, type 1a and 1b, have been described and
they seem to mediate different actions in different tissues.
In addition to their functions on growth hormone (GH) secretion
and food intake, ghrelin and its receptor are involved in
several cardiovascular mechanisms, pancreatic functions, adipogenesis,
gonadal function, immune system actions or tumoral cells.
This review will summarize data regarding the structure of
the GHS-R gene, reports investigating the expression, control
and functions of the GHS-R in various tissues, and studies
of the underlying transcriptional mechanisms and the genetic
manipulation of both ghrelin and GHS-R. Thus, it seems clear
the possibility that ghrelin and/or GHS analogs, acting as
either agonists or antagonists on different activities, might
have clinical impact.
[Back to top]
D1
and Functionally Selective Dopamine Agonists as Neuroprotective
Agents in Parkinson’s Disease
M.M. Lewis, X. Huang1, D.E. Nichols and R.B. Mailman
Parkinson’s disease (PD) is a progressive neurodegenerative
disorder that results in major motor disturbances due primarily
to loss of midbrain dopamine neurons. The mainstream treatment
has been dopaminergic replacement therapy aimed at symptomatic
relief, with the gold standard drug being the dopamine precursor
levodopa. The general dogma has been that levodopa works primarily
by indirectly activating the D2
family of dopamine receptors. Recently, a number of direct
dopamine agonists that target the D2
and D3
dopamine receptors have been used as dopaminergic replacement
strategies. Although these direct D2
and D3
drugs cause only modest improvement in motor function compared
to levodopa, they can delay the initiation of levodopa and
can act synergistically with levodopa. In addition, they can
delay the onset of levodopa-related motor complications. Recent
imaging data also suggest that they may have neuroprotective
effects. Whereas D2/D3
agonists have received much attention as several drugs are
available for clinical trials and usage, there has been a
large body of data showing that the D1
receptor actually may play a larger role in restoration of
normal motor function. This review examines the current use
of dopamine D2/D3
agonists in treatment of PD and their potential for providing
neuroprotection. Furthermore, we also examine the potential
that D1
agonists might have in neuroprotective actions in the disease
progression.
[Back to top]
Signaling Mechanisms Underlying Aβ
Toxicity: Potential Therapeutic Targets for Alzheimer’s
Disease
Wanli W. Smith, Myriam Gorospe and John W. Kusiak
The accumulation of amyloid β
peptide (Aβ)
is believed to be an early and critical event leading to synapse
and neuronal cell loss in Alzheimer’s Disease (AD).
Aβ
itself is toxic to neurons in vitro and the load
of Aβ
in vivo causes the loss of synapses and neurons in
brain in animal models. Therefore, there has been considerable
interest in elucidating the mechanism(s) of Aβ
neurotoxicity. Here, we review the molecular signaling pathways
involved in Aβ-induced
cell death, including signaling through the neuronal nicotinic
receptor and the Aβ-triggered
generation of reactive oxygen species (ROS) leading to the
activation of the c-jun N-terminal kinase (JNK), and the ensuing
phosphorylation of p66Shc and inactivation of the Forkhead
transcription factors. This focused review not only provides
a better understanding of the signaling mechanisms involved
in Aβ-induced
cell death, but also underscores the potential of JNK, p66Shc,
Forkhead proteins, p25/cdk5, and neuronal nicotinic receptor,
as therapeutic targets for AD.
[Back to top]
The Vitamin D Neuroendocrine System as a Target for Novel
Neurotropic Drugs
A.V. Kalueff, A. Minasyan, T. Keisala, M. Kuuslahti, S.
Miettinen and P. Tuohimaa
Vitamin D is a seco-steroid hormone with multiple functions
in the nervous system. Physiological brain mechanisms of vitamin
D and its receptors include neuroprotection, antiepileptic
effects, immunomodulation, possible interplay with several
brain neurotransmitter systems and hormones, as well as the
regulation of behaviours. Here we review the important role
of the vitamin D neuroendocrine system in the brain, and outline
perspectives for the search for novel neurotropic drugs to
treat various vitamin D-related dysfunctions.
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