[Frontiers in Bioscience S4, 461-488, January 1, 2012]

Histamine receptor subtypes: a century of rational drug design

Miriam Walter1, Holger Stark1

1Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biocenter, ZAFES/LiFF/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Histamine H1 receptor
3.1. Histamine H1 receptor agonists
3.2. Histamine H1 receptor antagonists
4. Histamine H2 receptor
4.1. Histamine H2 receptor agonists
4.2. Histamine H2 receptor antagonists
5. Histamine H3 receptor
5.1. Histamine H3 receptor agonists
5.2. Histamine H3 receptor antagonists
6. Histamine H4 receptor
6.1. Histamine H4 receptor agonists
6.2. Histamine H4 receptor antagonists
7. Computational methods
8. Perspective
9. Acknowledgments
10. References

1. ABSTRACT

Histamine plays an important role as neurotransmitter and chemical mediator in multiple physiological and pathophysiological processes in central and peripheral tissues. In the last century the extensive study of its actions in the human body, resulted in the identification of four G protein-coupled receptor (GPCR) subtypes (H1R-H4R), mediating numerous effects. The successful application of H1R and H2R antagonists/inverse agonists in the treatment of allergic conditions and gastric ulcer proved that these two receptors are excellent drug targets. Ligands for H3R are currently in advanced stages of clinical development for a broad spectrum of mainly central diseases (e.g. narcolepsy, Alzheimer's disease, epilepsy and schizophrenia). Meanwhile, preclinical research in the H4R field, focused on inflammatory and immunological processes, led to the evaluation of the first H4R-targeting clinical candidates. Drug development for each histamine receptor subtype will be discussed with a special focus on H3R and H4R ligands.