Histamine pharmacology: from Sir Henry Dale to the 21st century

Abstract

Histamine has been one of the most studied substances in medicine, playing a major role in diverse (patho)physiological processes. It elicits its multifaceted modulatory functions by activating four types of GPCRs, designated as H_1-4 . Despite the heterogeneity and the complexity of histamine receptor pharmacology, many discoveries over the past 100 years resulted in the development of H₁ antihistamines and H₂ -targeting 'blockbuster' therapeutics for the management of allergies and gastrointestinal disorders respectively. Recently, a first-in-class H₃ inverse agonist was approved for the treatment of narcolepsy, whereas H₄ antagonists are under clinical evaluation for their potential therapeutic exploitation in immune-related diseases. This review critically presents the past successes and drawbacks in histamine research, complemented by the modern conceptual innovations in molecular and receptor pharmacology. It targets both young and experienced researchers in an ongoing effort to stimulate novel insights for the dissection of the translational potential of histamine pharmacology. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Figure 1

Timeline of the major achievements in histamine research and in the therapeutic exploitation of histamine receptor (H₁–H₄) ligands. HDC, histidine decarboxylase; HNMT, histamine N‐methyltransferase.

Figure 2

Overview of the main functions of the histamine receptors. Histamine is formed in various cell types (rectangular box) and orchestrates numerous actions via binding to four receptor types, designated as H₁–H₄. Ga_s, Ga_i/o, Ga_q/11: G protein Ga subunits.

Figure 3

Historical features of the EHRS portraying the Honorary and Late Honorary Members and illustrating in chronological order the members who served as Secretary‐General and President of the Society since 1972. Honorary membership is the highest award of the EHRS, only given to very special people who contributed significantly to the Society and histamine research (EHRS, 2018). The members' place of work is shown in brackets. The EHRS logo is presented in the bottom left hand corner.