Current Topics in Medicinal Chemistry - Volume 6, Issue 18, 2006

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. Muller, 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. Andres (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 Medicine Pitie Salpetriere, 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. Muller (Heinrich-Heine-Universitat, Dusseldorf, Germany); D. A. Smelson (UMDNJ- Robert Wood Johnson Medical School, Piscataway, NJ, USA); E. Vermeulen (Center for Pharmacy, State University, Groningen, The Netherlands).

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.

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 nonpatent 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.

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.

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.

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 nonsteroidal 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.

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.

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.

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 intraarticular 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.