Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 11, 2007
Contents
Melanocortin Receptor Ligands and Their
Potential Therapeutic Uses
Guest Editor: Ning Xi
Editorial Pp. 1040-1041
Molecular Modeling of Melanocortin Receptors
Pp. 1042-1051
Hongmao Sun and David Fry
[Abstract]
Structure-Activity Relationships of β-MSH
Derived Melanocortin-4 Receptor Peptide Agonists
Pp. 1052-1067
Liang Zeng Yan, Hansen M. Hsiung, Mark L. Heiman, Robert
A. Gadski, Paul J. Emmerson, JeAnne Hertel, David Flora, Patrick
Edwards, Dave Smiley, Lianshan Zhang, Saba Husain, Steven
D. Kahl, Richard D. DiMarchi and John P. Mayer
[Abstract]
Small Molecule Ligands of the Human Melanocortin-4
Receptor Pp. 1068-1084
Feroze Ujjainwalla and Iyassu K. Sebhat
[Abstract]
Design, Synthesis and Biological Evaluation of Ligands
Selective for the Melanocortin-3 Receptor Pp. 1085-1097
Victor J. Hruby, Minying Cai, James P. Cain, Alexander
V. Mayorov, Matthew M. Dedek and Devendra Trivedi
[Abstract]
Melanocortin Receptors as Targets in the Treatment
of Obesity Pp. 1098-1110
Daniel D. Lam, I. Sadaf Farooqi and Lora K. Heisler
[Abstract]
Melanocortin Receptors, Melanotropic Peptides and
Penile Erection Pp. 1111-1119
Stephen H. King, Alexander V. Mayorov, Preeti Balse-Srinivasan,
Victor J. Hruby, Todd W. Vanderah and Hunter Wessells
[Abstract]
Therapeutic Application of Melanocortin-4 Receptor
Ligands
Guest Editor: John P. Mayer
Editorial Pp. 1120
Melanocortin - 4 Receptor Agonists for the Treatment
of Obesity Pp. 1121-1130
Paul J. Emmerson, Matthew J. Fisher, Liang Zeng Yan and
John P. Mayer
[Abstract]
Melanocortin-4 Receptor Antagonists as Potential Therapeutics
in the Treatment of Cachexia Pp. 1131-1136
Alan C. Foster and Chen Chen
[Abstract]
Melanocortins in the Treatment of Male and Female
Sexual Dysfunction Pp. 1137-1144
Annette M. Shadiack, Shubh D. Sharma, Dennis C. Earle,
Carl Spana and Trevor J. Hallam
[Abstract]
Melanocortin-4 Receptor Antagonists for the Treatment
of Depression and Anxiety Disorders Pp. 1145-1151
Shigeyuki Chaki and Taketoshi Okubo
[Abstract]
Molecule
of Month
Abstracts
[Back to top]
Editorial
Melanocortin receptors (MCRs) belong to the superfamily of
7-transmembrane G-protein coupled receptors (GPCRs). Five
MCR subtypes, named MC1-5 receptors, have been identified
and cloned to date. The identification of hypothalamic melanocortin
receptors, MC3R and MC4R, as central components of feeding
behavior and metabolism have helped build a picture, albeit
incomplete, of the neuronal pathways involved in energy homeostasis.
Thus, the intervention of neural MCR pathway may be a viable
way to treat metabolic disorders such as obesity. Neural MCRs
also participate in the regulation of sexual function, thus
providing an alternative, centrally mediated therapeutic approach
for erectile and other sexual dysfunctions. To this end, MC3/4R
agonists and antagonists based on peptide, peptidomimetic,
and small molecule structures have been prepared and evaluated
for their biological activities. This, in turn, has enhanced
our understandings on the physiological functions of the central
melanocortin system.
This special issue of “Current Topic in Medicinal Chemistry”
is organized to highlight recent advances in the field of
melanocortins. Six articles from researchers involved in the
investigation of MCR ligands and their potential therapeutic
uses are included.
Hongmao Sun and David Fry start the issue with an in-depth
review on the molecular modeling of melanocortin receptors.
The understanding of how a MCR ligand interacts with each
MCR subtype is essential to design potent, selective MCR ligands.
In their article, Sun and Fry describe three molecular modeling
approaches for MCRs, i.e., structure-based, ligand-based methods
and proteochemometrics. The strengths and limitations of these
approaches are evaluated. The authors conclude that the determination
of the high resolution X-ray crystal structure of bovine rhodopsin
(a GPCR with structure closely related to MCR), the availability
of many selective MC4R agonists and the mature proteochemometrics
all provide better than ever useful information to assist
the design of potent and selective MCR ligands.
The next three articles are focused on the design and synthesis
of potent, selective MC3R and MC4R ligands. First, Liang Zeng
Yan, Hansen M. Hsiung, Mark L. Heiman, Robert A. Gadski, Paul
J. Emmerson, JeAnne Hertel, David Flora, Patrick Edwards,
Dave Smiley, Lianshan Zhang, Saba Husain, Steven D. Kahl,
Richard D. DiMarchi, and John P. Mayer from Eli Lily present
their work on MC4R agonists based on the native β-MSH(5-22)
sequence. Optimization efforts led them to identify a novel
series of disulfide constrained hexapeptides that showed improved
potency in binding MC4R and enhanced selectivity over MC1R.
These cyclic peptides also demonstrated in vivo efficacy
in reducing food intake in animal feeding models. The next
article describes the recent development of small molecule-based
MC4R agonists and antagonists. During the discussion of small
molecule MC4R agonists, Feroze Ujjainwalla and Iyassu K. Sebhat
divide the subject into two portions: rational peptidomimetic
design which includes privileged structure approach, as well
as cyclization and molecular modeling approaches; and hit
to lead discovery of MC4R agonists. Their insightful structural
analysis of MC4R ligands will benefit anyone who is interested
in this field. In the following review, Professor Victor J.
Hruby, Minying Cai, James P. Cain, Alexander V. Mayorov, Matthew
M. Dedek and Devendra Trivedi discuss the biological functions
attributed to the MC3R, and summarize the efforts to design
and synthesize ligands that are potent and selective for the
MC3R. Various linear and cyclic peptide templates based on
α-,
β-,
and γ-MSH,
as well as several peptidomimetic and small molecule design
approaches leading to potent and selective hMC3R agonists
and antagonists are provided.
It is now well established that melanocortin-containing neurons
are nutritionally regulated and that genetic alterations in
the melanocortin system produce profound effects on food intake,
energy expenditure, and body weight. This is a heavily researched
area and new findings are fast growing. In their article on
MCR and obesity, Daniel D. Lam, I. Sadaf Farooqi and Lora
K. Heisler examine the mechanisms of melanocortin regulation
on energy balance. The effects of various hormones such as
leptin, insulin, neuropeptide Y, etc. on neural melanocortins
are discussed, and the importance of the endogenous ligand
β-MSH
in human is recognized. The authors also describe the results
from preclinical and clinical studies of melanocortin receptor
agonists and antagonists. Based on these studies, they indicate
that lack of persistent effects with chronic administration
and undesirable side-effects are obstacles to the successful
clinical implementation of drugs targeting melanocortin receptors
in the treatment of obesity. Various promising strategies
are being pursued to overcome these limitations, including
the synthesis of more selective and potent melanocortin analogues.
It is interesting to note that MCR agonists are developed
initially without intention to be used based on their proerectile
effects. However, preclinical and clinical studies show that
MC3/4R agonists are promise as therapeutic agents to enhance
sexual function in human males and females. In fact, a cyclic
peptide-based MCR agonist, PT-141 (Bremelanotide®)
is currently in the clinical trials for the treatment of erectile
dysfunction. In the last review of this issue, Stephen H.
King, Alexander V. Mayorov, Preeti Balse-Srinivasan, Victor
J. Hruby, Todd W. Vanderah, and Hunter Wessells provide a
perceptive review on this important therapeutic application
of MCR agonists. They discuss the roles of both central MCRs,
i.e., MC3R and MC4R, in mediating erection. In connection
to this subject, the authors provide preliminary results from
their laboratory in assessing the contributions of central
MC3R to erection. They emphasize that in contrast to the current
therapies for erectile dysfunction which target end organ
vascular tissue, MCR agonists provide an alternative, centrally
mediated therapeutic approach for erectile and other sexual
dysfunctions. Thus, further detailed studies are necessary
to understand the role of melanocortinergic signaling in normal
erectile function, and its potential perturbation by disease
states associated with erectile dysfunction.
Finally, I wish to thank Dr. Allen B. Reitz for inviting me
to be the Guest Editor of this special issue. I would like
to thank all the eminent authors who have contributed to this
issue. This collection of timely reviews could not be finished
without their hard work and dedication. I am indebted to them
for their diligent efforts.
Ning Xi
Chemistry Research & Discovery
One Amgen Center Drive
Thousand Oaks, CA 91320
USA
[Back to top]
Molecular Modeling of Melanocortin Receptors
Hongmao Sun and David Fry
Molecular modeling of G-protein coupled receptors (GPCRs)
remains a challenge due to the limited availability of structural
information for the receptors. Molecular modeling approaches
for melanocortin receptors (MCRs) fall into three categories:
structure-based, ligand-based, and proteochemometric. Homology
modeling combined with the information obtained from site-directed
mutagenesis of receptors, recombined chimeric mutations of
receptors and the structures of melanocortin type 4 receptor
(MC4R) peptide ligands, has provided insights on detailed
ligand-receptor interactions. Still, homology models based
on the structures of bacteriorhodopsin (bR) or bovine rhodopsin
as templates have not reached atomic level accuracy, making
them unsuitable for rational drug design. On the other hand,
availability of a large number of potent ligands of MCRs,
especially those for the therapeutically important MC4R, has
fueled ligand-based approaches, including automated pharmacophore
query optimization and pharmacophore-based virtual screening.
Proteochemometrics, a novel technology for the analysis of
intermolecular interactions between ligand and receptor, has
also shown great value in obtaining detailed informaton on
molecular recognition and providing guidance to ligand design.
In this review, the strengths and limitations of homology
modeling, pharmacophore modeling and proteochemometrics modeling
of MCRs are evaluated.
[Back to top]
Structure-Activity Relationships of β-MSH
Derived Melanocortin-4 Receptor Peptide Agonists
Liang Zeng Yan, Hansen M. Hsiung, Mark L. Heiman, Robert
A. Gadski, Paul J. Emmerson, JeAnne Hertel, David Flora, Patrick
Edwards, Dave Smiley, Lianshan Zhang, Saba Husain, Steven
D. Kahl, Richard D. DiMarchi and John P. Mayer
The recent emergence of obesity as a major health threat in
the industrialized world has intensified the search for novel
and effective pharmacologic treatment. The proopiomelanocortin
(POMC)-melanocortin 4 receptor (MC4R) axis has been shown
to regulate food intake and energy homeostasis and is considered
among the most promising antiobesity targets. Our initial
efforts in this area have focused on affinity and selectivity
directed optimization of the native β-MSH(5-22)
sequence and resulted in the discovery of a potent MC4R agonist:
Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH2
(10). Subcutaneous administration of this
peptide produced an excellent in vivo efficacy in
reducing food intake and increasing fat metabolism. Additionally,
suppression of food intake was observed in wild type but not
in MC4R deficient mice, suggesting that the effects observed
in the wild type mice were mediated through MC4R signaling.
Subsequent optimization efforts led to the identification
of a novel series of disulfide constrained hexapeptides as
exemplified by Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH2
(100). These cyclic hexapeptides showed a
further improved potency in binding MC4R and an enhanced selectivity
over MC1R. At a dose of 0.07 mg/kg analog 102
reduced food intake by 38% and increased fat utilization by
58% in rats. These cyclic peptides provide novel and enhanced
reagents for the elucidation of melanocortin receptors biology
and may find applications in the treatment of obesity and
related metabolic disorders.
[Back to top]
Small Molecule Ligands of the Human Melanocortin-4
Receptor
Feroze Ujjainwalla and Iyassu K. Sebhat
Genetic and pharmacological studies, involving both animals
and humans, suggest that the central MC4 receptor plays a
key role in homeostatic control, most probably via
regulation of appetite and energy expenditure. This has stimulated
intense research efforts in the field of drug discovery to
identify MC4 receptor agonists and antagonists for the therapeutic
treatment of obesity and diseases associated with loss of
body weight. This article constitutes a near comprehensive
review of the published scientific literature on small molecule
ligands of the hMC4 receptor since 2002.
[Back to top]
Design, Synthesis and Biological Evaluation of Ligands
Selective for the Melanocortin-3 Receptor
Victor J. Hruby, Minying Cai, James P. Cain, Alexander
V. Mayorov, Matthew M. Dedek and Devendra Trivedi
The processed products of the proopiomelanocortin gene (ACTH,
α-MSH,
β-MSH,
γ-MSH,
etc.) interact with five melanocortin receptors, the MC1R,
MC2R, MC3R, MC4R, and MC5R to modulate and control many important
biological functions crucial for good health both peripherally
(as hormones) and centrally (as neurotransmitters). Pivotal
biological functions include pigmentation, adrenal function,
response to stress, fear/flight, energy homeostasis, feeding
behavior, sexual function and motivation, pain, immune response,
and many others, and are believed to be involved in many disease
states including pigmentary disorders, adrenal disorders,
obesity, anorexia, prolonged and neuropathic pain, inflammatory
response, etc. The melanocortin-3 receptor (MC3R) is found
primarily in the brain and spinal cord and also in the periphery,
and its biological functions are still not well understood.
Here we review some of the biological functions attributed
to the MC3R, and then examine in more detail efforts to design
and synthesize ligands that are potent and selective for the
MC3R, which might help resolve the many questions still remaining
about its function. Though some progress has been made, there
is still much to be done in this critical area.
[Back to top]
Melanocortin Receptors as Targets in the Treatment
of Obesity
Daniel D. Lam, I. Sadaf Farooqi and Lora K. Heisler
The central melanocortin system plays a critical role in energy
homeostasis. It is well established that melanocortin-containing
neurons are nutritionally regulated and that genetic alterations
in the melanocortin system produce profound effects on food
intake, energy expenditure, and body weight. Within the brain,
melanocortin-producing neurons originate in the arcuate nucleus
of the hypothalamus (ARC) and the nucleus of the solitary
tract (NTS) in the brainstem and project to various nuclei
modulating energy balance. A large body of pharmacological
and genetic evidence implicates the central melanocortin 4
receptors (MC4Rs) in the effects of melanocortin peptides
on ingestive behaviour, energy expenditure, and body weight.
Preclinical studies with endogenous and synthetic melanocortin
ligands demonstrate that they produce potent effects on food
intake and energy expenditure. Clinical studies thus far have
been somewhat less successful and have been hampered by the
induction of side effects, which present obstacles to the
development of successful therapeutic agents. However, various
promising strategies are being pursued to overcome these limitations,
including the synthesis of more selective and potent melanocortin
analogs.
[Back to top]
Melanocortin Receptors, Melanotropic Peptides and
Penile Erection
Stephen H. King, Alexander V. Mayorov, Preeti Balse-Srinivasan,
Victor J. Hruby, Todd W. Vanderah and Hunter Wessells
Penile erection is a complex physiologic event resulting from
the interactions of the nervous system on a highly specialized
vascular organ. Activation of central nervous system melanocortinergic
(MC) receptors with either endogenous or synthetic melanotropic
ligands may initiate and/or facilitate spontaneous penile
erection.
While the CNS contains principally the MC3 and MC4 receptor
subtypes, there is conflicting data as to which receptor mediates
erection. Although the MC4R is emerging as the principle effector
of MC induced erection, the role of the MC3R is poorly understood.
Manipulation of each receptor subtype with newly synthesized
receptor specific agonists and antagonists, as well as knockout
mice, has elucidated their individual contributions. Novel
data from our laboratories suggests that antagonism of forebrain
MC3R may enhance melanocortin-induced erections. Furthermore,
melanocortin agents may interact with better-studied systems
such as oxytocinergic pathways at the hypothalamic, brainstem
or spinal level.
Current therapies for erectile dysfunction target end organ
vascular tissue. Manipulation of MC receptors may provide
an alternative, centrally mediated therapeutic approach for
erectile and other sexual dysfunctions. The non-specific “superpotent”
MC agonist, PT-141, which is the carboxylate derivative of
MT-II, has reached phase II human trials. Through their centrally
mediated activity, melanocortin agonists have potential to
treat erectile dysfunction as well as possible applications
to the unmet medical needs of decreased sexual motivation
and loss of libido.
[Back to top]
Editorial
From the initial discovery of its role in amphibian skin pigmentation
to the more recently established involvement in multiple physiological
processes such as food intake, energy balance, inflammation,
sexual function, depression and anxiety, the history of the
melanocortin system represents one of the more important chapters
in pituitary endocrinology. Although certain therapeutic applications
were foreseeable decades ago, it was only following the cloning,
expression and biological characterization of the MC-1 through
MC-5 receptor subtypes in the early 1990’s that the
scientific community began to contemplate the full therapeutic
utility of the melanocortin pathway. While each of the five
receptor subtypes represents a potential drug target, the
MC-4 receptor (MC-4R) subtype has received by far the greatest
share of interest and visibility. In this issue of Current
Topics in Medicinal Chemistry we have focused on four
MC-4R related therapeutic indications which have received
considerable recognition.
1) Extensive preclinical and clinical evidence suggests that
the MC-4R subtype is intimately involved in the control of
food intake and energy expenditure. Numerous animal studies
with either melanocortin ligands or transgenic rodents have
implicated the involvement of this receptor in food intake
and body weight regulation. The correlation of mutations in
the human MC-4R with obesity has reinforced these preclinical
findings and suggested that stand alone or adjunctive administration
of a MC-4R agonist may be beneficial in anti-obesity therapy.
Progress in this area is summarized by Paul Emmerson and co-workers
from Eli Lilly and Co.
2) Based on the above preclinical and clinical validation,
an equally convincing argument can also be made for the use
of MC-4R antagonists for the treatment of conditions characterized
by caloric deficit such as cachexia and anorexia resulting
from cancer or AIDS. In these scenarios, the down regulation
of MC-4R signaling could offer an important treatment option.
This therapeutic approach has been validated in a number of
animal models of tumor-induced wasting. The rationale and
progress in this area is reviewed by Alan Foster and Chen
Chen from Neurocrine Biosciences.
3) Treatment of male and female sexual dysfunction represents
another potential therapeutic indication for MC-4R agonists.
Stimulation of penile erection has been demonstrated with
selective MC-4R agonists in a number of rodent models. More
importantly, a statistically significant erectile response
has been shown clinically upon intranasal or subcutaneous
administration of bremelanotide, PT-141, a nonselective melanocortin
agonist. Additionally, these agents may also be useful in
the treatment of female sexual arousal disorder. These indications
are updated by Annette Shadiack and co-workers from Palatin
Technologies.
4) The potential utility of MC-4R antagonists in the treatment
of CNS disorders is highlighted through application to anxiety
and depression. The key observation that melanocortin agonists
produce stress-induced grooming behavior in rodents which
is reversible through administration of a selective antagonist
prompted exploration of this pathway for the treatment of
anxiety and depression. This novel therapeutic concept is
reviewed by Shigeyuki Chaki and Taketoshi Okubo from the Taisho
Pharmaceutical Company.
John P. Mayer, Ph.D
Paul J. Emmerson, Ph.D
Lilly Research Laboratories
Lilly Corporate Center
Indianapolis, IN 46285
USA
[Back to top]
Melanocortin - 4 Receptor Agonists for the Treatment
of Obesity
Paul J. Emmerson, Matthew J. Fisher, Liang Zeng Yan and
John P. Mayer
The melanocortin family of receptors (MC 1 – 5R) and
their endogenous peptide ligands (α,
β,
γ- MSH and ACTH) have been implicated in the control
of a wide variety of behavioral and physiological functions
including the homeostatic control of food intake and body
weight. In rodent models, melanocortin agonists including
the nonselective peptide MTII have been shown to decrease
food intake and body weight while antagonists such as SHU9119
and AGRP have been shown to stimulate food intake and increase
body weight. Deletion of either the MC3R or MC4R in mice was
found to be associated with obesity although hyperphagia was
only observed in the MC4R deficient mice. Similarly in humans,
inactivating mutations of the MC4R have been found in as many
as six percent of obese individuals. The suggestion from these
findings that activation of MC4Rs would have an anorectic
effect in humans has resulted in efforts to produce selective
agonists for the treatment of obesity. Over the past decade,
efforts to develop MC4R selective small molecule and peptide
agonists have been met with fractional success. Many small
molecule agonists have been identified; however, few have
been shown to have activity in vivo. While their
use as therapeutics may have limitations, selective and potent
peptide agonists have been shown by several investigators
to decrease food intake and body weight in rodent models.
The subject of the current review is to examine the progress
made to date on producing both small molecule and peptide
MC4R agonists as potential therapeutics for obesity.
[Back to top]
Melanocortin-4 Receptor Antagonists as Potential Therapeutics
in the Treatment of Cachexia
Alan C. Foster and Chen Chen
The melanocortin-4 (MC4) receptor subtype plays a pivotal
role in body weight regulation. Knock-out or mutation of MC4
receptors in animals or humans leads to severe obesity and
acute or sub-acute antagonism of central MC4 receptors produces
an increase in food intake and a decrease in metabolism. Knock-out
or antagonism of MC4 receptors in animal models of cachexia
leads to a protection from anorexia and the loss of both lean
and fat body mass, suggesting that an MC4 antagonist may be
beneficial in wasting diseases, which are poorly treated by
available therapies. Considerable progress has been made in
the discovery of non-peptide antagonists with high affinity
and selectivity for MC4 receptors. Optimization of these compounds
has produced molecules that are active upon systemic administration
and are effective in protecting against cachectic symptoms
in animal models of tumor-induced wasting. Further development
of such compounds is greatly anticipated as a potential means
to combat the cachexia that results from chronic diseases
such as cancer, AIDS, renal failure, liver failure, congestive
heart failure and lung disease.
[Back to top]
Melanocortins in the Treatment of Male and Female
Sexual Dysfunction
Annette M. Shadiack, Shubh D. Sharma, Dennis C. Earle,
Carl Spana and Trevor J. Hallam
Melanocortinergic agents are currently being investigated
for a possible therapeutic role in male and female sexual
dysfunction. These investigations were sparked by findings
that systemic administration of a synthetic analog of alpha-MSH,
MT-II, causes penile erections in a variety of species, including
humans. Several other melanocortinergic agents including HP-228,
THIQ, and bremelanotide (PT-141) have since been shown to
have erectogenic properties thought to be due to binding to
melanocortin receptors in the central nervous system, particularly
the hypothalamus. Bremelanotide, a nasally administered synthetic
peptide, is the only melanocortinergic agent that has been
clinically studied in both males and females. Data from Phase
II clinical trials of bremelanotide support the use of melanocortin-based
therapy for erectile dysfunction. Studies using animal models
have demonstrated that pre-copulatory behaviors in female
rats analogous to sexual arousal are evoked, and preliminary
clinical data also suggest a role in promoting sexual desire
and arousal in women. Based on bremelanotide clinical experience,
administration of a melanocortin agonist is well tolerated
and not associated the hypotension observed with phosphodiesterase-5
inhibitors currently used to treat erectile dysfunction. This
review discusses investigations of melanocortin agonists for
the treatment of sexual dysfunction with emphasis on proposed
sites and mechanisms of action in the central nervous system
that appear to be involved in melanocortinergic modulation
of sexual function. Current research validates use of melanocortinergic
agents for the treatment of both male and female sexual dysfunction.
[Back to top]
Melanocortin-4 Receptor Antagonists for the Treatment
of Depression and Anxiety Disorders
Shigeyuki Chaki and Taketoshi Okubo
Derived from proopiomelanocortin by proteolytic processing,
melanocortins have been implicated in a wide range of physiological
processes. Melanocortins exert their physiological effects
by binding to specific receptors on the surface of cell membranes.
To date, five subtypes of melanocortin receptors (MC1 –
MC5) have been identified, all of which are G-protein coupled
receptor whose activation leads to increase in intracellular
cyclic 3',5'-adenosine monophosphate formation. Of these,
the MC4 receptor is expressed predominantly throughout the
central nervous system, particularly, in areas related to
stress responses and emotional states. Expression of the MC4
receptor is regulated by stress exposure. Reports also indicate
that stimulation of the MC4 receptor activates the hypothalamus-pituitary-adrenal
axis, and that the MC4 receptor mediates stress-related behaviors
and anxiety in rodents.
Recently developed selective MC4 receptor antagonists have
demonstrated antidepressant and anxiolytic effects in several
animal models of depression and anxiety. MC4 receptor antagonists
are effective, particularly under conditions of high stress,
which may be consistent with the etiology of depression and
anxiety. This review describes the involvement of the MC4
receptor in stress response and discusses the potential value
of MC4 receptor antagonists for the treatment of stress-related
disorders such as depression and anxiety.
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