ReviewThe neuronal 5-HT3 receptor network after 20 years of research — Evolving concepts in management of pain and inflammation☆
Introduction
20 years after the first characterization of a so-called selective 5-HT3-antagonist the time has come to re-examine the acknowledged concepts and rate critically new perspectives for this compound class.
In the early 1990s the introduction of 5-HT3-receptor antagonists into the market was perceived as a tremendous step forward to combat chemotherapy-induced emesis. This great success transiently dampened the attention to other treatment areas like psychiatric diseases and pain management where clinical development of these compounds originally had started. During the last years researchers increasingly turned back to the beginnings, encouraged by promising results in challenging indications like fibromyalgia and irritable bowel syndrome.
This review focuses on recent investigations on the pharmacology of the 5-HT3 receptor with its embedding in a complex neurotransmitter network and the recently emerging promising indications for 5-HT3-receptor antagonists.
Section snippets
Structure
Among the seven known classes of serotonin receptors the 5-HT3 receptor occupies a special place: it is phylogenetically much older than the other serotonin receptors, all of which have developed from a single primordial 5-HT receptor and belong to the G-protein coupled receptors. In contrast, the 5-HT3 receptor is a ligand-gated cation channel belonging to the nicotine/gamma-amino-butyrate (GABA) receptor super-family, and it shares structural and functional features with other members of this
5-HT3-receptor ligands — is receptor selectivity of ‘setrons’ an outdated concept?
Application of 5-HT3-receptor agonists like 2-methyl-5-hydroxytryptamine and meta-chlorophenylbiguanide (mCPBG) causes unfavourable effects like nausea and anxiety. No clinical use is targeted at present.
Six 5-HT3-receptor antagonists are currently available on the market (further compounds are in the pipeline): tropisetron, ondansetron, granisetron, dolasetron, palonosetron and alosetron. All of these are highly potent compounds which can induce complete competitive blockade of peripheral and
New perspectives in clinical use of 5-HT3-receptor antagonists
Blockade of the 5-HT3 receptors in animal models does not modify normal behavioural patterns, and the only changes observed in physiological functions in healthy volunteers are a certain prolongation of intestinal transit time and discrete, clinically insignificant changes in cardiac conduction, but no evidence of particular CNS effects.
In certain pathological conditions, however, central and/or peripheral 5-HT3-receptor blockade has very pronounced effects. Significance of 5-HT3-receptor
Conclusion
The synthesis of 5-HT3-receptor antagonists 20 years ago resulted in a milestone in supportive cancer therapy since chemotherapy-induced emesis was suppressed far more effectively than with any other drug. The dominating idea at that time was that of a highly selective compound class with mainly gastrointestinal effects. During the last two decades it has been replaced by a concept of drugs which interfere with complex central nervous processes, which show immunomodulatory functions and which
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Preparation of the manuscript was supported by Novartis Pharma GmbH, Nuremberg.