Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 18, 2006
Contents
Serotonin Receptors as Targets in Drug
Discovery and Medicinal Chemistry
Guest Editor: Dr. Marcello Leopoldo
Editorial Pp. 1907
Central Serotonin2C
Receptor: From Physiology to Pathology Pp. 1909-1925
Giuseppe Di Giovanni, Vincenzo Di Matteo, Massimo Pierucci,
Arcangelo Benigno and Ennio Esposito
[Abstract]
Selective Agents for Serotonin2C (5-HT2C)
Receptor Pp. 1927-1970
Enza Lacivita and Marcello Leopoldo
[Abstract]
Serotonin 5-HT2A and 5-HT2C Receptors
as Potential Targets for Modulation of Psychostimulant Use
and Dependence Pp. 1971-1985
Marcy J. Bubar and Kathryn A. Cunningham
[Abstract]
Serotonergic Modulation of Spinal Sensory Circuits
Pp. 1987-1996
José A. Lopez-Garcia
[Abstract]
The Role of 5-HT1A Receptors in Research Strategy
for Extensive Pain Treatment Pp. 1997-2003
Juan A. Mico, Esther Berrocoso, Antonio Ortega-Alvaro,
Juan Gibert-Rahola and M. Olga Rojas-Corrales
[Abstract]
Pharmacophore Models for Metabotropic 5-HT Receptor Ligands
Pp. 2005-2026
Andrzej J. Bojarski
[Abstract]
PET and SPECT Molecular Imaging: Focus on Serotonin System
Pp. 2027-2034
Rosa Maria Moresco, Mario Matarrese and Ferruccio Fazio
[Abstract]
New Treatment Options Using 5-HT3 Receptor
Antagonists in Rheumatic Diseases Pp. 2035-2042
Wolfgang Müller, Bernd L. Fiebich and Thomas Stratz
[Abstract]
Abstracts
[Back to top]
Editorial
Serotonin (5-HT) is a widely distributed
neurotransmitter and hormone in the mammalian central nervous
system and periphery. In 1957 Gaddum and Picarelli reported
the characterization of two distinct receptors for serotonin,
namely M and D receptors. Since then, several other serotonin
receptors have been identified and characterized. Starting
from 1988, with the advent of molecular cloning techniques,
fourteen receptors of serotonin have been cloned from several
species.
After nearly fifty years of intense research efforts, witnessed
by the introduction into the market of serotonergic drugs
such as buspirone, ondansetron, ketanserine, and paroxetine
among many others, one could ask whether it is still worth
studying the serotonin system. Clearly, the answer is yes.
From a search of Scifinder® database on July 2005, it
emerged that among the 5-HT receptors, the 5-HT2C
subtype was the object of intense research. Drs. G. Di Giovanni,
V. Di Matteo, M. Pierucci, A. Benigno and E. Esposito present
a review on the pharmacological characteristics of this receptor,
whereas Drs. E. Lacivita and M. Leopoldo offer an overview
on the studies carried out in both pharmaceutical companies
and academy aimed to the identification of selective agents
for 5-HT2C receptor. The review by Drs. M. J. Bubar
and K. A. Cunningham focus on one of the most promising therapeutic
application for 5-HT2C and 5-HT2A receptor
agents, namely the treatment of psychostimulant addiction
in humans.
The role of 5-HT in pain mechanisms has been evidence nearly
twenty years ago. Recently, several 5-HT receptor subtypes
have been localized into the spinal cord. These new findings
have supported the involvement of serotonin receptors in pain
mechanisms. Dr. J. A. Lopez-Garcia has reviewed electrophysiological
observations from spinal neurons using local administration
of serotonergic agents. The review by Drs. J. A. Mico, E.
Berrocoso, A. Ortega-Alvaro, J. Gibert-Rahola, and M. O. Rojas-Corrales
focuses on 5-HT1A receptors as a target in the
search of new pharmacological approaches in the augmentation
of analgesia.
The 5-HT3 receptor has been the target for the
develovepment of several drugs for chemotherapy induced emesis
therapy. Starting from the clinical use of such agents some
other potential therapeutic uses for 5-HT3 receptor
antagonist have emerged. Drs. W. Müller, B. L. Fiebich,
and T. Stratz have reviewed their physiology–driven
studies on new treatment options in rheumatic diseases using
5-HT3 receptor antagonists.
The last two reviews are important updates on studies performed
in the field of serotonergic agents. In particular, the review
by Dr. A. Bojarski provide a detailed overview on the pharmacophore
models proposed up-to-date for the serotonergic receptors.
The review by A. M. Moresco, M. Materrese, and F. Fazio describes
the state of the art in the discovery of PET and SPET radioligands
for the in vivo visualization of serotonin receptors.
I am very grateful to all the above contributors for their
excellent reviews and I hope readers will enjoy this issue.
Finally, I’d like to thank those who have critically
read the manuscripts: Drs. J. I. Andrés (Johnson &
Johnson Pharmaceutical R&D, Toledo, Spain); K. A. Berg
(University of Texas Health Science Center, San Antonio, TX,
USA); J.-F. Bernard (Faculté de Médicine Pitié
Salpêtrière, Paris, France); M. Ernberg (OFA,
Karolinska Institutet, Stockholm, Sweden); P. J. Fletcher
(Departments of Psychiatry and Psychology, University of Toronto,
Canada); M. Iskander (Monash University, Victorian College
of Pharmacy, Parkville, Australia); Y. Kawakami (Tokyo Women’s
Medical Center, Tokyo, Japan); O. Langer (Medical University,
Vienna, Austria); M. L Lopez-Rodriguez, (Facultad de Ciencias
Quimicas, Universidad Complutense, Madrid, Spain); J. Lundberg
(Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden); C. Müller (Heinrich-Heine-Universität,
Düsseldorf, Germany); D. A. Smelson (UMDNJ- Robert Wood
Johnson Medical School, Piscataway, NJ, USA); E. Vermeulen
(Center for Pharmacy, State University, Groningen, The Netherlands).
Marcello Leopoldo
Università degli Studi di Bari,
Dipartimento Farmaco-Chimico,
via Orabona, 4,
70125, Bari,
Italy
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Central Serotonin2C
Receptor: From Physiology to Pathology
Giuseppe Di Giovanni, Vincenzo Di Matteo, Massimo Pierucci,
Arcangelo Benigno and Ennio Esposito
Since the 1950s, when serotonin (5-HT) was discovered in the
mammalian central nervous system (CNS), an enormous amount
of experimental evidence has revealed the pivotal role of
this biogenic amine in a number of cognitive and behavioural
functions. Although 5-HT is synthesized by a small group of
neurons within the raphe nuclei of the brain stem, almost
all parts of the CNS receive serotonergic projections. Furthermore,
the importance of 5-HT modulation and the fine-tuning of its
action is underlined by the large number of 5-HT binding sites
found in the CNS. Hitherto, up to 15 different 5-HT receptors
subtypes have been identified.
This review was undertaken to summarize the work that has
explored the pathophysiological role of one of these receptors,
the 5-HT2C receptor, that has been emerged as a
prominent central serotonin receptor subtype. The physiology,
pharmacology and anatomical distribution of the 5-HT2C
receptors in the CNS will be firstly reviewed. Finally, their
potential involvement in the pathophysiology of depression,
schizophrenia, Parkinson’s disease and drug abuse will
be also discussed.
[Back to top]
Selective Agents for Serotonin2C (5-HT2C)
Receptor
Enza Lacivita and Marcello Leopoldo
The serotonin2C (5-HT2C) receptor has
attracted a lot of attention owing to its role in appetite
regulation, depression, obsessive-compulsive disorder (OCD),
panic disorders, and substance abuse. This review summarizes
non-patent and patent literature up to November 2005 that
deals with the synthesis and characterization of selective
5-HT2C receptor agonists and antagonists. Highlights
on structure-activity relationships have been included, when
possible.
[Back to top]
Serotonin 5-HT2A and 5-HT2C Receptors
as Potential Targets for Modulation of Psychostimulant Use
and Dependence
Marcy J. Bubar and Kathryn A. Cunningham
The development of novel pharmacological agents for the treatment
of psychostimulant use disorders is an important research
imperative. One potential target system that has been largely
overlooked is the serotonin (5-HT) neurotransmitter system.
Preclinical studies indicate that 5-HT may be important in
modulating the reinforcing properties of various drugs of
abuse. While the potential sites of action of 5-HT within
the brain are extensive, the natural starting point to examine
the mechanisms by which 5-HT may be useful in treatment of
psychostimulant use disorders is the interaction between 5-HT
and dopamine (DA), a primary mediator of the “rewarding”
effects of psychstimulants. Two key modulators of DA output
are the serotonin (5-HT)2A receptor (5-HT2AR)
and the 5-HT2CR. These receptors are known to control
the neurochemical and behavioral effects of psychostimulants,
and in particular, the in vivo effects of cocaine.
Preclinical studies indicate that 5-HT2AR antagonists
and/or 5-HT2CR agonists may effectively
reduce craving and/or relapse, and likewise, enhance abstinence,
while 5-HT2CR agonists may also effectively
reduce cocaine intake in active cocaine users. At present,
the progression of studies to probe the effectiveness of 5-HT2AR
and 5-HT2CR ligands in the clinical setting is
hindered by a lack of available selective 5-HT2AR
antagonists or 5-HT2CR agonists for use in human
cocaine abusers. However, a number of selective 5-HT2R
ligands currently under development, or in early clinical
trials for psychiatric and/or neurological disorders, may
soon be available for translational studies to explore their
effectiveness in modulating drug use and dependence.
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Serotonergic Modulation of Spinal Sensory Circuits
José A. Lopez-Garcia
The role of serotonin (5-HT) as a mediator of the endogenous
pain control system has been investigated over the last 30
years. Here we review a subset of studies that used electrophysiological
techniques to study the mechanisms of action as well as the
receptors mediating the spinal effects of serotonin. The works
herein discussed employed in vivo or in vitro
preparations of control or hyperalgesic animals.
According to these reports, 5-HT triggers depressant effects
on synaptic transmission limiting the release of neurotransmitters
from afferent terminals or the responsiveness of NMDA receptors
located in dorsal horn neurones. These mechanisms are most
likely mediated by 5-HT1 receptors. In contrast,
5-HT2 receptors seem to mediate excitatory effects
such as depolarisation, increased excitability, and neurotransmitter
release. The role of 5-HT3 receptors is less clear
as they could mediate excitatory or inhibitory effects, depending
on variables such as concentration of 5-HT or the state (sensitised/unsensitised)
of the spinal cord.
The consequences of these spinal effects of serotonin are
discussed in the context of pain and analgesia.
[Back to top]
The Role of 5-HT1A Receptors in Research Strategy
for Extensive Pain Treatment
Juan A. Mico, Esther Berrocoso, Antonio Ortega-Alvaro,
Juan Gibert-Rahola and M. Olga Rojas-Corrales
In the last few years, there has been a great increase in
our understanding of pain mechanisms. Given the complexity
of the mechanisms involved in pain modulation, it is surprising
that the pharmacological control of pain through the application
of relatively simple analgesics can be effective. Nevertheless,
the application of single analgesics is not always effective
in diverse painful conditions such as chronic pain syndromes.
In these circumstances, we can take advantage of the complexity
of pain regulation and try to identify new targets in these
intricate processes. It is becoming clear that the combination
of different mechanisms, which improves efficacy with reduced
toxicity, is necessary for the reliable pharmacotherapy of
pain, and is at the forefront in the search for better analgesics.
Serotonin is involved at multiple levels in the regulation
of nociception. In particular, the raphe nuclei may play a
crucial role in integrating the nociceptive and affective
information through descending projections to the spinal cord
and ascending projections to the forebrain. In these nuclei,
5-HT1A receptors function as somatodendritic autoreceptors
controlling the release of serotonin in terminal areas. Different
studies have shown that, by preventing this inhibitory control
of serotonin release, it is possible to enhance the analgesic
effect of drugs that increase serotonin levels (i.e. antidepressants,
opiates, and non-steroidal anti-inflammatory drugs) by facilitating
descending, and also ascending, pathways involved in pain
modulation. Therefore, 5-HT1A receptors may be
used as a new target in the search for new pharmacological
approaches in the augmentation of analgesia.
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Pharmacophore Models for Metabotropic 5-HT Receptor Ligands
Andrzej J. Bojarski
An overview of pharmacophore models, developed for different
subtypes of serotonin receptors belonging to the GPCR family,
is presented. Starting with early models for 5-HT1A
and 5-HT2 receptor ligands, and ending with the
latest ones for 5-HT6-and 5-HT7 receptors,
as many as fifty others are briefly summarized. No models
have been developed for 5-HT1F-, 5-HT2B-
and 5-HT5B receptor ligands, and in the case of
5-HT1E- and 5-HT5ARs only single pilot
studies with non-selective tryptamine derivatives are reported.
For all the other subtypes of 5-HTRs, various pharmacophore
hypotheses – either qualitative and/or quantitative
– are characterized by sets of ligands used for their
generation, a templates for alignment, the computational methods
applied and, eventually, interfeature distances and/or statistical
results – if available.
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PET and SPECT Molecular Imaging: Focus on Serotonin System
Rosa Maria Moresco, Mario Matarrese and Ferruccio Fazio
Emission tomography techniques and, in particular, positron
emission tomography (PET) enable the in vivo study
of several physiological and neurochemical variables in human
subjects using methods originally developed for quantitative
autoradiography. In particular, PET allows one to evaluate
in human subjects: (a) the effect of specific neurochemical
challenges on regional brain function at rest or under activation;
(b) the activity of neurotransmitters and the regional expression
of specific molecular targets during pathology including their
modulation by drug treatment; (c) the kinetics of drug disposition
and activity directly in the target organ. This is of primary
interest in the field of biological psychiatry and in psychoactive
drugs development, where it is particularly difficult to reproduce
human diseases using animal models in view of the peculiarity
of this field and the large heterogeneity of each psychiatric
illness also inside the same clinical definition. The aim
of this paper is to review the principal strategies and the
main results of the use of PET or single photon emission tomography
(SPET) molecular imaging for the in vivo study of
serotonin receptors and the main results obtained from their
application in the study of major depression.
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New Treatment Options Using 5-HT3 Receptor
Antagonists in Rheumatic Diseases
Wolfgang Müller, Bernd L. Fiebich and Thomas Stratz
In vitro studies have shown that a blockade
of 5-HT3
receptors brings about a reduction of tumor necrosis factor,
IL-1 beta, IL-2, IL-6 as well as a decrease in prostaglandins.
Clinical trials have provided evidence of pain reduction in
a subgroup of fibromyalgia syndrome and, moreover, have demonstrated
that tropisetron injected locally for insertion tendinoses
and myofascial syndromes with associated trigger points leads
to an alleviation of pain that is comparable to injections
with the combination of corticosteroids and local anesthetics.
The effects achieved by intra-articular injections in cases
of osteoarthritis and rheumatoid arthritis paralleled those
exerted by intraarticular injection of corticosteroids. In
addition, the positive effects produced by systemically administered
tropisetron on scleroderma need to be considered since they
suggest that this therapeutic principle can also be applied
systemically in immunologic processes.
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