Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 17, 2007
Contents
Neuropeptide Y Receptors as Targets in
Drug Discovery
Guest Editor: Ambikaipakan Balasubramaniam
Editorial Pp. 1644
Relevance of Neuropeptide Y (NPY) in Psychiatry
Pp.1645-1659
Katherine Eaton, Floyd R. Sallee and Renu Sah
[Abstract]
Clinical Potential of Neuropeptide Y Receptor Ligands
in the Treatment of Epilepsy Pp. 1660-1674
Alfred Meurs, Ralph Clinckers, Guy Ebinger, Yvette Michotte
and Ilse Smolders
[Abstract]
Global Life-Long Health Benefits of Repression of
Hypothalamic NPY System by Central Leptin Gene Therapy
Pp. 1675-1681
Satya P. Kalra
[Abstract]
Relevance of the Neuropeptide Y System in the Biology
of Cancer Progression Pp. 1682-1691
M. Ruscica, E. Dozio, M. Motta and P. Magni
[Abstract]
NPY and Cardiac Diseases Pp.1692-1703
B. J. McDermott and D. Bell
[Abstract]
NPY and NPY Receptors in Vascular Remodeling
Pp. 1704-1709
Ken Abe, Jason U. Tilan and Zofia Zukowska
[Abstract]
NPY Family of Hormones: Clinical Relevance and Potential
Use in Gastrointestinal Disease Pp. 1710-1720
L. C. Vona-Davis and D. W. McFadden
[Abstract]
NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity
Drugs Pp. 1721-1733
Douglas J. MacNeil
[Abstract]
NPY Y2 and Y4
Receptors Selective Ligands: Promising Anti Obesity Drugs?
Pp. 1734-1742
M.M. Kamiji and A. Inui
[Abstract]
NPY and Receptors in Immune and Inflammatory Diseases
Pp. 1743-1752
Julie Wheway, Herbert Herzog and Fabienne Mackay
[Abstract]
Molecule
of Month Pp. 1753
Abstracts
[Back to top]
Editorial
My daughter was borne in 1980, surely a good omen! At about
the same time, I joined the University of Cincinnati as a
fellow, and was looking for a new project in the GI hormone
field and, coincidentally Tatemoto, the Man with Gold Fingers,
added neuropeptide Y (NPY) and peptide YY (PYY) to his long
list of polypeptide hormone discoveries. Since then, I have
been working on NPY family of hormones and NPY peptides which,
in turn, have served me well to date. The latter may also
be true for most of my colleagues all over the world, who
are privileged to meet every couple of years at the International
Meetings on NPY. To be honest, I do not know much of anything
else other thanbeyond NPY, Cincinnati, and my family!
NPY (isolated from brain), PYY (isolated from intestine) and
pancreatic polypeptide (PP) (isolated from pancreas) constitute
the NPY/PP family of homologous hormones. Since its isolation,
NPY has been described in various ways, depending on the site
and function investigated. Some of these characterizations
reveal normally reserved scientists reaching for superlatives:
“NPY is the most abundant peptide in the brain;”
“NPY is the most potent vasoconstrictor peptide isolated
to date,” “NPY is the most powerful orexigenic
peptide isolated to date.” These remarkable properties
of NPY, especially the latter, spurred vigorous investigation
of the properties of the NPY family of hormones. The last
two and a half decades have seen the cloning of four functional
receptors, denoted Y1, Y2,
Y4 and Y5,
the development of several useful receptor-specific
ligands and the establishment of knock-out models for NPY
and its various receptors.
These tools have played key roles in delineating the receptor
subtypes mediating various actions of NPY and also have provided
strong evidence for the involvement of the NPY family of hormones
in the pathophysiology of various conditions including obesity,
cardiovascular and cardiac diseases, intestinal dysfunction,
epilepsy and mental disorders. Thus, NPY receptors became
obvious targets for drug development in the treatment of a
variety of diseases. Moreover, a few pharmaceutical companies
have recently initiated preliminary clinical or Phase I trials
to determine whether NPY peptides have potential as anti-obesity
drugs. For these reasons, the time is now appropriate for
a special volume of Current Topics in Medicinal Chemistry
dedicated to the “Potential of NPY Receptors as Targets
in Drug Discovery.”
In compiling this Special Volume on NPY, I have gathered contributions
from experts on receptor targets that have been implicated
unequivocally in diseases. In addition, I have also included
chapters on emerging drug targets. A total of ten articles,
including chapters on the clinical potential of NPY and its
receptors in mental disorders, obesity, epilepsy, GI disorders,
cancer, cardiac and cardiovascular diseases, and inflammatory
and immune diseases are included in this volume. One of these
chapters also describes how central leptin gene therapy could
be exploited to beneficially alter hypothalamic NPY function.
After a brief introduction, each chapter, based on the existing
evidence, discusses the rationale(s) for developing NPY-based
drugs, the receptor subtypes involved and the type of ligands
(agonist/antagonist) that need to be developed. Most chapters
conclude with a prospective of using NPY-based drugs to treat
the concerned disease.
In summary, this state-of-the-art volume on NPY Receptors
as Targets for Drug Discovery will not only stimulate further
research on the Clinical Potential of NPY, but will also serve
as a “One-Stop Guide” on NPY-based drugs for those
entering this field. I am certain that, with the advancement
in peptidic- and non-peptidic drug delivery techniques, NPY
based drugs will eventually be developed to treat a variety
of diseases. I wish to express my sincere appreciation to
all the authors for their outstanding contributions, and particularly
for meeting their deadlines. I also thank Allen Reitz, Editor-in
Chief, for asking me to edit this Special Volume on NPY.
Ambikaipakan Balasubramaniam, Ph.D.
Professor, Department of Surgery
University of Cincinnati College of Medicine
Cincinnati, OH 45267-0558
USA
[Back to top]
Relevance of Neuropeptide Y (NPY) in Psychiatry
Katherine Eaton, Floyd R. Sallee and Renu Sah
Extensive preclinical studies suggest neuropeptide Y (NPY)
to be involved in stress regulation and coping. NPY counteracts
the behavioral consequences of stress and anxiety to maintain
emotional homeostasis. NPY is also involved in learning, memory,
and cognition, all of which are dysregulated in many psychiatric
states. Dense localization of NPY and NPY receptors is found
in brain areas implicated in psychopathology such as the amygdala,
hippocampus, neocortex, septum, caudate-putamen, hypothalamus
and locus coeruleus. Impaired central NPY signaling may therefore
be involved in the pathophysiology of depression, anxiety,
schizophrenia, alcoholism, and trauma-induced disorders like
PTSD. Studies on the readily accessible plasma from psychiatric
patients have provided some information on the relevance of
NPY as a marker for sympathetic tone in certain conditions.
Reports on cerebrospinal fluid (CSF) NPY in subjects with
depression indicate a dysregulation of central NPY in this
disorder, however, other conditions still need to be investigated.
[Back to top]
Clinical Potential of Neuropeptide Y Receptor Ligands
in the Treatment of Epilepsy
Alfred Meurs, Ralph Clinckers, Guy Ebinger, Yvette Michotte
and Ilse Smolders
A substantial amount of experimental evidence implicates neuropeptide
Y (NPY) in the pathophysiology of epilepsy. Over the past
20 years, remarkable progress has been made in unraveling
the mechanisms and receptors involved in the anticonvulsant
effect of this abundantly expressed neuropeptide. Activation
of Y2 and/or Y5
receptors and blockade of Y1
receptors in the central nervous system suppresses seizures
in a variety of animal seizure models. Orally available, brain
penetrating Y2 and/or Y5
agonists, and possibly Y1
antagonists, may therefore constitute a novel class of antiepileptic
drugs, which could greatly benefit patients with medically
refractory epilepsy. Significant progress has been made in
identifying non-peptidergic Y1
antagonists that fulfill these criteria, but suitable Y2
and/or Y5 agonists have proven
to be more elusive. Innovative oral and parental drug delivery
strategies which are currently under development may offer
a means of using the more readily available peptidergic NPY
receptor ligands in a clinical setting. Finally, gene therapy,
antisense probes or RNA interference strategies which alter
the expression of NPY or its receptors in specific brain regions
may also be of use in the treatment of epilepsy, but will
probably benefit a smaller subgroup of epilepsy patients,
since they typically require an invasive procedure.
[Back to top]
Global Life-Long Health Benefits of Repression of
Hypothalamic NPY System by Central Leptin Gene Therapy
Satya P. Kalra
A minute-to-minute crosstalk between the hypothalamic neuropeptide
Y (NPY) network and the hormone leptin is essential for energy
homeostasis. Leptin insufficiency i.e. lack of leptin restraint
due to genetic and environmental factors on the hypothalamic
NPY system confers obesity, a cluster of metabolic afflictions
and shorter lifespan. A state-of-the-art gene transfer technology
using recombinant adeno-associated viral vector to overcome
hypothalamic leptin insufficiency was employed in rodent models
of obesity, metabolic syndrome and shorter lifespan. Our findings
show that life-long tonic repression of NPY system with a
stable increase in leptin availability in the hypothalamus
prevented the age-related and high fat-diet-induced obesity,
hyperinsulinemia and diabetes and extended lifespan. Additional
health benefits include increased energy expenditure and normalization
of neuroendocrine control on reproduction, and promotion of
brain and bone growth. We propose that central leptin gene
transfer therapy or novel long-acting leptin mimetics should
be tested clinically to decelerate the worldwide epidemic
of obesity, diabetes and shortened lifespan.
[Back to top]
Relevance of the Neuropeptide Y System in the Biology
of Cancer Progression
M. Ruscica, E. Dozio, M. Motta and P. Magni
The peptides pancreatic polypeptide (PP), peptide YY (PYY),
and neuropeptide Y (NPY) share a similar structure, known
as PP-fold. Within this family of peptides, NPY, a highly
conserved 36-aminoacid residue peptide, is involved in the
regulation of a wide range of physiological functions, such
as food intake and energy metabolism, as well as in the promotion
of some remarkable aspects of tumor progression, including
cell proliferation, matrix invasion, metastatization, and
angiogenesis. NPY exerts its biological effects through five
G-protein coupled receptors, named Y1-, Y2-, Y4-, Y5-, and
y6-R, which appear associated with different aspects of oncogenesis.
Y1-R seems involved in the modulation of cancer cell proliferation,
whereas Y2-R activation appears to promote angiogenesis. The
development of NPY receptor subtype selective analogs has
helped to elucidate the physiological and pathophysiological
role and localization of each receptor and may contribute
to a better understanding of the receptor-ligand interaction.
The NPY system appears to be variously associated with specific
tumors, including neural crest-derived tumors, breast and
prostate cancers. In addition to NPY, PYY is also able to
affect cancer cell growth in a dose-dependent manner and through
Y-Rs. In conclusion, peptides of the NPY family and the related
receptors play an important role in the progression of different
cancer types, with some molecular specificity according to
each step of this process. On this basis, future studies may
be directed to the implementation of novel diagnostic and
therapeutic approaches targeting this system.
[Back to top]
NPY and Cardiac Diseases
B. J. McDermott and D. Bell
Hypertension-induced left ventricular hypertrophy (LVH), along
with ischemic heart disease, result in LV remodeling as part
of a continuum that often leads to congestive heart failure.
The neurohormonal model has been used to underpin many treatment
strategies, but optimal outcomes have not been achieved. Neuropeptide
Y (NPY) has emerged as an additional therapeutic target, ever
since it was recognised as an important mediator released
from sympathetic nerves in the heart, affecting coronary artery
constriction and myocardial contraction. More recent interest
has focused on the mitogenic and hypertrophic effects that
are observed in endothelial and vascular smooth muscle cells,
and cardiac myocytes. Of the six identified NPY receptor subtypes,
Y1, Y2
and Y5 appear to mediate
the main functional responses in the heart. Plasma levels
of NPY become elevated due to the increased sympathetic activation
present in stress-related cardiac conditions. Also, NPY and
Y receptor polymorphisms have been identified that may predispose
individuals to increased risk of hypertension and cardiac
complications. This review examines what understanding exists
regarding the likely contribution of NPY to cardiac pathology.
It appears that NPY may play a part in compensatory or detrimental
remodeling of myocardial tissue subsequent to hemodynamic
overload or myocardial infarction, and in angiogenic processes
to regenerate myocardium after ischemic injury. However, greater
mechanistic information is required in order to truly assess
the potential for treatment of cardiac diseases using NPY-based
drugs.
[Back to top]
NPY and NPY Receptors in Vascular Remodeling
Ken Abe, Jason U. Tilan and Zofia Zukowska
Neuropeptide Y (NPY) is a sympathetic neurotransmitter that
acts on multiple receptors (Y1-Y6) and exerts a variety of
cardiovascular effects. Originally known as a vasoconstrictor
acting on Y1 receptors, NPY is also a potent angiogenic factor
as well as a powerful stimulator of vascular smooth muscle
proliferation and atherogenesis in vitro and in
vivo. These two types of vascular remodeling are predominantly
mediated by Y2/Y5 and Y1 receptors respectively, but evidence
suggests that all receptors are activated in both conditions.
A strategy to inhibit neointima formation and atherosclerotic
lesions without impairing ischemic angiogenesis and collateral
vessel formation has been a major challenge to overcome. Studies
in rodents show that Y1 receptor antagonist inhibits angioplasty-induced
atherosclerotic-like vascular remodeling, without affecting
ischemic revascularization. Conversely, Y2 receptor activation
appears to be sufficient to stimulate angiogenesis in various
animal models. Thus, the use of selective receptor agonists
to promote angiogenesis through the Y2 receptor while antagonizing
the pro-atherosclerotic and pro-stenotic effects with Y1 receptor-selective
antagonists may help to successfully treat vascular remodeling
in cardiovascular diseases.
[Back to top]
NPY Family of Hormones: Clinical Relevance and Potential
Use in Gastrointestinal Disease
L. C. Vona-Davis and D. W. McFadden
The neuropeptide Y (NPY), peptide YY (PYY) and pancreatic
polypeptide (PP) family of hormones exhibit a wide variety
of biological actions on the mammalian gastrointestinal tract
through known G-protein coupled receptor pathways. At least
four receptor subtypes, denoted as Y1,
Y2, Y4
an Y5, each with specific
affinities to NPY ligands, serve as regulators of mucosal
function, gastrointestinal motility and secretion. Investigations
to date, however, have implicated the NPY peptides as mediators
in the pathogenesis of numerous gastrointestinal disorders,
including malabsorption, short gut, inflammatory bowel diseases,
and forms of pancreatitis. Our understanding of these diseases
and the interactions of NPY peptides have been advanced by
the development of receptor agonists and antagonists that
can be used experimentally in animal models. Potent selective
PYY agonists have been developed that exhibit clinical potential
as proabsorptive agents. NPY receptor agonists and antagonists
as well as mice harboring null mutations in the Y1
and Y4 receptors have provided
novel approaches in preventing intestinal inflammation and
diarrhea. The use of competitive antagonists and Y2
receptor knockouts have also aided in understanding secretory
tone and electrogenic ion transport in the colon. In the pancreas,
PYY suppresses amylase and cytokine release, which would be
desirable in the clinical therapy of pancreatitis. Protein/DNA
array analysis has revealed that PYY reduces transcription
factor binding activity and disrupts signal transduction pathways
activated by TNF-α
in acinar cells. The present review gives an overview
of NPY research in gastrointestinal disease and discusses
its clinical relevance and potential use as therapy.
[Back to top]
NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity
Drugs
Douglas J. MacNeil
A combination of pharmacological and genetic studies in mice
confirmed that the Y1 and Y5 receptors mediate the potent
orexigenic actions of exogenous NPY. Although the physiological
role of NPY in causing obesity is less clear, potent and selective
antagonists of both Y1 and Y5 have been developed. Some of
the NPY antagonists have suitable pharmokinetic (PK) properties
that allowed them to be evaluated in various rodent models
of obesity. Several different Y1 and Y5 antagonists cause
weight loss in rodent models, though confirmation that these
effects are mechanism based has been limited. One Y5 antagonist,
MK-0557 was evaluated in a 1-yr clinical trial and found to
cause modest weight loss. Optimal NPY antagonist therapeutics
for obesity may require blockade of both the Y1 and Y5 receptors.
[Back to top]
NPY Y2 and Y4
Receptors Selective Ligands: Promising Anti Obesity Drugs?
M.M. Kamiji and A. Inui
Neuropeptide Y (NPY), a potent orexigen peptide widely produced
and distributed in arcuate neurons in the hypothalamus, is
a promising candidate for the control of appetitive ingestive
behavior. In mammals, the signaling is mediated via at least
five different cell surface receptors, denoted as Y1,
Y2, Y4,
Y5 and Y6.
Obesity is an important public health problem in the world,
particularly in developed societies, and has taken on pandemic
proportions. The therapeutics of obesity, including appetite
suppressants, has increased 453% over the past decade, although
issues concerning safety, efficacy, and little knowledge of
the pharmacological activity result in the still modest effects
of the anti-obesity drugs presently used. Ligands for Y receptors
may be of benefit for the treatment of obesity, and recent
findings have indicated a promising role of Y2
and Y4 in protecting against
diet-induced obesity. This review highlights the supporting
evidence therapeutic potential of Y2
and Y4 receptors antagonists
as additional intervention to treat human obesity.
[Back to top]
NPY and Receptors in Immune and Inflammatory Diseases
Julie Wheway, Herbert Herzog and Fabienne Mackay
Growing evidence suggests that neuropeptide Y (NPY) plays
an important role in the immune system. NPY is produced by
the central and peripheral nervous system but also by immune
cells in response to activation. NPY has pleiotropic effects
on both the innate and adaptive arms of the immune system,
with effects ranging from the modulation of cell migration
to macrophage, T helper (Th) cell cytokine release, and antibody
production. Subsequent studies have confirmed the importance
of this system in immunity in particular via the demonstration
that Y1, a receptor for NPY, plays a fundamental role in autoimmunity
and inflammation using Y1-deficient animals. Furthermore,
clinical studies have suggested a role for NPY in other immune
disorders such as asthma and arthritis. This review provides
the latest information on the role of NPY and Y1 in the immune
system, and discusses the potential new opportunities of this
work for the development of a new generation of immuno-modulatory
treatments of autoimmune and inflammatory diseases.
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