Current Topics in Medicinal Chemistry - Volume 10, Issue 5, 2010

Progress in the recent past has allowed examining in detail the actions and mechanisms of naturally occurring and newly synthesised molecules and their interactions with receptor proteins. As part of our understanding in neuronal communication, knowledge of serotonin (5-hydroxytryptamine, 5-HT) receptors has also expanded tremendously in the last twenty years. The powerful techniques of molecular cloning have revealed a broad diversity of serotonin receptors and their subtypes. The enormous amount of work performed in this field has led to the identification of seven different serotonin receptors and the various subtypes of 5-HT1 and 5-HT2 receptors. The extent of research carried out is justified by the fact that serotonin acts as a neurotransmitter in the central nervous system and influences a number of neuroregulator actions in the periphery, in smooth muscle contraction, in the operation of the cardiovascular and gastrointestinal organs, and in platelet functions. Neuroscience research in serotonin receptors has provided the potential to identify newly synthesised compounds acting on these receptors. Drug development in medicinal chemistry is always an exciting procedure but we all know how futile these efforts can be. Chemical synthesis and preclinical screening of serotonin receptor ligands with their inherent difficulties are no exception either. In the present issue we intend to summarize where we are at present in the discovery of serotonin-like compounds. This volume focuses on recent developments and most importantly on key discoveries to the ligands of various serotonin receptor subtypes. Chapters of this volume provide exhaustive reviews not only of specific serotonin receptor ligands but also of their relevance to health and disease. Moreover, the reader will find chapters discussing compounds acting on the serotonin receptor at multiple sites of action, or acting also on serotonin transporter or histamine receptors. The contributors of this special issue are all distinguished scientists who have gathered on a common platform and contributed their knowledge to a summary of the medicinal chemistry of serotonin receptor ligands. We believe that their efforts were a success and a pleasurable experience. We are particularly thankful for the magnitude, clarity and explicitness of the authors' descriptions of the basic principles of medicinal chemistry. This volume can also act as an excellent guide for introducing the subject to the investigators. It is recommended to chemists, neuroscientists and molecular biologists who are interested in the medical chemistry of serotonin research. We hope that this issue will be of valuable assistance and will provide further stimulation to those engaged in laboratory work.

This article highlights recent advances in the discovery of new agonists, antagonists and partial agonists of the 5-HT1D receptor. The field of 5-HT1D agonists continues to deliver a number of new potential therapeutic agents, although advances in this field are now more focussed on the clinical evaluation phase. The identification of novel compounds is greater for the 5-HT1D receptor antagonists, and whilst few truly selective ligands have been identified, a number of approaches are discussed towards defined mixed-pharmacology profiles. An overview is also given of recent advances in biological and clinical understanding of the receptor.

5-HT2B receptors have been reported to play an important role at cardiac, intestinal and central levels, as well as in bone marrow formation and growth. In the last decade, 5-HT2B receptors have also gained much attention as new targets in therapeutics, but also as off-targets because their activation along with the inhibition of serotonin transporters plays a significant role in the pathogenesis of 5-HT induced valvulopathy. Taking this into account, the present review focuses on the new therapeutic applications of 5-HT2B receptor ligands as well as on the potential concerns.

The 5-HT3 receptor (5-HT3R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT3R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT3R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is mainly focused on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years.

This article reviews the medicinal implications of 5-HT4R in the peripheral and central nervous systems, based on data from two hundred bibliographic references. An exhaustive compilation of molecules reported to be antagonists or agonists for 5-HT4R is presented, including chemical structures, binding properties and pharmacological profiles. In the last part of the review, some key concepts concerning structure-activity relationships are highlighted.

Although the 5-HT5 receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The Gi/G0-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT1 receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT5 receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological effects, thus its ligands are potential drug candidates in various areas, e.g. anxiety, sleep, incontinence, food intake, learning and memory, pain or chemoreception pathways. These findings have motivated several institutes and pharmaceutical companies to participate in the research of this field. Despite extensive research, no selective agonist and only two selective antagonists have been identified until now. Beyond these compounds, the present review provides a complete overview on all other published 5-HT5A receptor ligands as well as on the structure, function, distribution, genetics and possible therapeutic applications of this receptor.

Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1- phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g. MS-245; 5) were described as the first examples of selective 5-HT6 receptor antagonists only ten years ago. Today, hundreds of compounds of seemingly diverse structure have been reported. The early antagonists featured an arylsulfonyl group leading to the widespread assumption that an arylsulfonyl moiety might be critical for binding and antagonist action. With respect to the arylsulfonyltryptamines, it seems that neither the “arylsulfonyl” nor the “tryptamine” portion of these compounds is essential for binding or for antagonist action, and some such derivatives even display agonist action. The present review describes many of the currently available 5-HT6 receptor ligands and, unlike prior reviews, provides a narrative of the thinking (where possible) that led to their design, synthesis, and evaluation. The arylsulfonyltryptamines are also used as the structural basis of attempts to relate various structure-types to one another to afford a better understanding of the overall structural requirements for 5- HT6 receptor binding.

Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H3 receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H3 receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H3 receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.