1521-0081/67/3/601–655$25.00 http://dx.doi.org/10.1124/pr.114.010249 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:601–655, July 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors Pertti Panula, Paul L. Chazot, Marlon Cowart, Ralf Gutzmer, Rob Leurs, Wai L. S. Liu, Holger Stark, Robin L. Thurmond, and Helmut L. Haas Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry (H.S.) and Institute of Neurophysiology, Medical Faculty (H.L.H.), Heinrich-Heine-University Duesseldorf, Germany; and Janssen Research & Development, LLC, San Diego, California (R.L.T.) Abstract ....................................................................................602 Downloaded from I. Introduction and Historical Perspective .....................................................602 II. Histamine H1 Receptor . ..................................................................604 A. Receptor Structure ......................................................................604 B. Signal Mechanisms . ..................................................................605 C. Anatomic Framework . ..................................................................608 D. Function. ..............................................................................609 at Open University Library on January 16, 2020 E. H1-Selective Ligands . ..................................................................610 F. Clinical Pharmacology ..................................................................612 III. Histamine H2 Receptor . ..................................................................613 A. Receptor Structure ......................................................................613 B. Signal Transduction Mechanisms. ......................................................614 C. Anatomic Framework . ..................................................................615 D. Function. ..............................................................................616 E. H2 Receptor-Selective Ligands...........................................................616 F. Clinical Pharmacology ..................................................................618 IV. Histamine H3 Receptor . ..................................................................619 A. Receptor Structure ......................................................................619 B. Signal Transduction Mechanisms. ......................................................622 C. Anatomic Framework . ..................................................................623 D. Function. ..............................................................................625 E. H3-Selective Ligands . ..................................................................627 1. Agonists. ............................................................................627 2. Antagonists. ........................................................................627 F. Clinical Pharmacology ..................................................................629 P.P. received financial support from The Academy of Finland, The Sigrid Juselius Foundation, The Finnish Foundation for Alcohol Studies and (previously) a lecture compensation from Abbot Laboratories. P.C. received financial support from Gedeon Richter and GSK, compensation from Abbott Laboratories for a lecture and consultancy support from Ziarco Pharma Ltd. M.C. is an employee of AbbVie. R.G. received support from DFG [German Research Foundation GU434/6-1] and project support by Johnson & Johnson. R.L. received financial support from the Netherlands Organisation for Scientific Research (NWO), Abbott Laboratories, Pfizer, and UCB Pharma, and is a founder of Griffin Discoveries. W.L.S.L. is a founder of Ziarco Pharma Limited. R.L.T. is an employee of Janssen Research & Development. H.S. is one of the inventors of pitolisant. NC-IUPHAR is supported in part by Wellcome Trust Grant 099156/Z/12/Z. Original work by P.P., P.C., R.G., R.L., and H.S. was supported by European Cooperation in Science and Technology Action BM0806. This review is dedicated to the memory of Professor Sir James Black, FRS, Nobel laureate, who died on 22 March 2010, and Professor Walter Schunack, who died on 6 April 2011. Address correspondence to: Helmut Haas, Institute of Neurophysiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. E-mail: [email protected]; or Pertti Panula, Institute of Biomedicine, Anatomy, and Neuroscience Center, University of Helsinki, Finland. E-mail: [email protected] dx.doi.org/10.1124/pr.114.010249. 601 602 Panula et al. V. Histamine H4 Receptor . ..................................................................630 A. Receptor Structure ......................................................................630 B. Signal Transduction Mechanisms. ......................................................632 C. Anatomic Framework . ..................................................................633 D. Function. ..............................................................................635 E. H4 Receptor-Selective Ligands...........................................................637 1. Agonists. ............................................................................638 2. Antagonists. ........................................................................638 F. Clinical Potential .......................................................................640 VI. Other Responses to Histamine . ............................................................642 A. Histamine-Gated Channels. ............................................................642 B. Allosteric Modulation of N-Methyl-D-Aspartate Receptor . ...............................643 VII. Future Perspectives ........................................................................643 Acknowledgments . ........................................................................644 References..................................................................................644 Abstract——Histamine is a developmentally highly of H2R-antagonists that revolutionized stomach ulcer conserved autacoid found in most vertebrate tissues. treatment. The crystal structure of ligand-bound H1Rhas Its physiological functions are mediated by four 7- rendered it possible to design new ligands with novel transmembrane G protein–coupled receptors (H1R, properties. The H3Risanautoreceptorandheteroreceptor H2R, H3R, H4R) that are all targets of pharmacological providing negative feedback on histaminergic and intervention. The receptors display molecular heterogeneity inhibition on other neurons. A block of these actions and constitutive activity. H1R antagonists are long promotes waking. The H4Roccursonimmuncompetent known antiallergic and sedating drugs, whereas the cells and the development of anti-inflammatory drugs is H2R was identified in the 1970s and led to the development anticipated. I. Introduction and Historical Perspective Histamine (1) is an endogenous biogenic amine distributed ubiquitously in the body being present in Histamine pharmacology has experienced a renais- high concentrations in the lungs, skin, and gastroin- sance over the last few decades, with the identification testinal tract (Fig. 1). Histamine is synthesized and and cloning of the histamine H and H receptors, 3 4 stored at high concentrations within granules in so which doubles the members of the histamine receptor " " family. This has led to a massive increase in our called professional cells, basophils and mast cells, understanding of the histamine systems in the whole where it is associated with heparin. Based on a sensi- tive high-performance liquid chromatography-mass body and recently resulted in the introduction of H3 spectrometry method, nonmast cell histamine occurs receptor and H4 receptor drug leads into late-stage clinical development, with an ever expanding range of at high concentrations in enterchromaffin-like cells in potential therapeutic applications. The molecular the stomach, lymph nodes, and thymus, with modest levels in the liver, lung, and in varicosities of the identification of the H3 receptor and H4 receptor, their attendant isoforms, and species variants have now histaminergic neurons in the brain (Zimmermann clarified to some degree the pharmacological heteroge- et al., 2011). Histamine acts as a neurotransmitter in neity reported in the 1990s, reviewed in the previous the nervous system and as a local mediator in the gut, Pharmacological Reviews article by Hill et al. (1997). skin, and immune system. Histamine brings about This present review is dedicated to two of the foremost complex physiologic changes, including neurotransmis- histamine receptor pharmacologists, Sir James Black sion, inflammation, smooth muscle contraction, dilatation and Walter Schunack, who sadly died at the beginning of capillaries, chemotaxis, cytokine production, and of 2010