Histamine Receptors Histamine on the Role of Histamine in Allergic Diseases
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Histamine Receptors Iwan de Esch and Rob Leurs Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands Dr. Iwan de Esch is an assistant professor and Prof. Rob Leurs is full professor and head of the Division of Medicinal Chemistry of the Leiden/Amsterdam Center of Drug Research (LACDR), VU University Amsterdam, The Netherlands. Since the seventies, histamine receptor research has been one of the traditional themes of the division. Molecular understanding of ligand-receptor interaction is obtained by combining pharmacology (signal transduction, proliferation), molecular biology, receptor modelling and the synthesis and identification of new ligands. Introduction which were useful in inhibiting pronounced symptoms 4 Histamine is one of the aminergic neurotransmitters of allergic conditions. However, the first generation and plays an important role in the regulation of H1 receptor antagonists that were developed for of several (patho)physiological processes. In treating allergies revealed distinct side effects such the mammalian brain histamine is synthesised as sedation. This particular physiological effect of the ligands was eliminated by structural modifications DRIVING RESEARCH FURTHER in restricted populations of neurons that are DRIVING RESEARCH FURTHER located in the tuberomammillary nucleus of the that prevent blood-brain-barrier penetration of the posterior hypothalamus.1 These neurons project drugs. The first generation as well as the more diffusely to most cerebral areas and have been recently developed antihistamines (originally termed 5 implicated in several brain functions (e.g. sleep/ antagonists but later reclassified as inverse agonists ) wakefulness, hormonal secretion, cardiovascular are clinically very successful and are widely available control, thermoregulation, food intake, and memory drugs. In 1991, the cDNA encoding a bovine H1 formation).2 In peripheral tissues, histamine is stored receptor protein was cloned after an expression 6 in mast cells, eosinophils, basophils, enterochromaffin cloning strategy in Xenopus oocytes. The deduced cells and probably also in some specific neurons. amino acid sequence revealed a 491 amino acid Mast cell histamine plays an important role in the protein of 56 kDa. Using the cDNA sequence encoding pathogenesis of various allergic conditions. After the bovine H1 receptor, the cDNA sequences and 3,7 8,9 mast cell degranulation, release of histamine leads to intronless genes encoding the rat, guinea-pig, 10,11 12 various well-known symptoms of allergic conditions human and mouse H1 receptor proteins were in the skin and the airway system. In 1937, Bovet cloned soon thereafter. These receptor proteins are and Staub discovered compounds that antagonise slightly different in length, highly homologous and the effect of histamine on these allergic reactions.3 do not show major pharmacological differences. Ever since, there has been intense research Analysis of the 5´-flanking region of the human, rat 7,8,10 devoted towards finding novel ligands with (anti-) and guinea-pig gene resulted in the identification histaminergic activity. This research field has been of several DNA-binding motifs, including potential fuelled by the consecutive discovery of four unique glucocorticoid responsive elements. The human 13 histamine receptor subtypes. Every receptor subtype H1 receptor gene resides on chromosome 3. The has a very distinct (patho)physiological role and all of H1 receptor belongs to the large family of GPCRs. them belong to the superfamily of G-protein-coupled The receptor is associated with the phospholipase C-catalysed formation of inositol 1,4,5-triphosphate receptors (GPCRs). The histamine H1 and H2 receptor subtypes have proven to be excellent drug targets. (IP3) and 1,2-diaylglycerol (DAG). Histamine induces production of inositol phosphates in several tissues Ligands for the histamine H3 receptor subtype are currently entering clinical studies and the recently (including brain, airway, intestinal and vascular 24 14 smooth muscle ) via Gαq protein activation. In other discovered histamine H4 receptor subtype is subject of intense preclinical research. tissues, activation of H1 receptors can also stimulate adenylyl cyclase and formation of cAMP. Not all details of this signalling pathway are understood, for The Histamine H1 Receptor example questions remain about the G protein and Until the seventies, histamine research focused 2+ 15 on the role of histamine in allergic diseases. This the involvement of Ca . In any case, alternative resulted in the development of several potent signalling pathways can be mediated by the histamine ‘antihistamines’ (e.g. mepyramine, see figure 1), H1 receptor. Recent results indicate that the functional heterogeneity can be ligand-directed.16 Tocris Bioscience Scientific Review Series Tocris Bioscience Scientific Review Series The histamine H1 receptor is a well established drug in many new, non-sedating H1 antagonists (e.g., target and has been thoroughly studied for decades. cetirizine, astemizole, fexofenadine and loratidine).4 Nevertheless, H1 receptor research continues to flourish as many new techniques and approaches The Histamine H Receptor are being developed by using this receptor as an The observation that the classical ‘antihistamines’ archetypical GPCR target. Most notably, in the last (i.e. H1 receptor inverse agonists) cannot antagonise few years, the histamine H1 receptor has been the all histamine-induced effects (e.g. at the stomach subject of various molecular biology studies (e.g., and the heart), led Ash and Schild in 1966 to propose large-scale overproduction17 and GPCR binding site 18 two distinct subtypes of histamine receptors: H1 and elucidation ), biophysical approaches (such as solid- 25 19 H2. This hypothesis became generally accepted state NMR ) and investigations towards the general 26 20,21 when Black et al succeeded in the synthesis of activation mechanisms of GPCRs. a series of new compounds (e.g. burimamide, Ligands for H1 Receptors cimetidine), which were able to block the effects Modification of the imidazole moiety of histamine has of histamine on the stomach and the heart. These been the most successful approach for obtaining H2 receptor antagonists proved to be very useful in 27 selective H1 agonists (figure 1). The presence of the the therapy of gastric ulcers. Gantz et al were the � τ tautomeric N -N system of the imidazole ring is not first to clone a cDNA encoding a 359 amino acid H2 obligatory, as reflected by the selective H1 agonists receptor. Using degenerate primers based on the 2-pyridylethylamine and 2-thiazolylethylamine. known sequence similarity of various GPCRs, the Substitution of the imidazole ring at the 2-position H2 receptor sequence was obtained from canine leads to relatively selective H1 agonists. For example, gastric parietal cDNA by PCR. Soon thereafter, the 2-(meta-halogenated) phenylhistamines are relatively intronless genes encoding the rat,28 human,29 guinea- 22 30 31 potent H1 receptor agonists at the guinea-pig ileum; pig and mouse H2 receptor were cloned by means however, these compounds act as partial agonists of homology screening. Identification of the promotor 23 in other systems. A wide array of potent and region of the human H2 receptor gene revealed the 4 selective H1 antagonists are available. Compounds existence of regulatory transcription sites and regions such as mepyramine (also called pyrilamine) and displaying stimulatory and inhibitory effects on gene 32 triprolidine are highly potent H1 antagonists and expression monitored in a luciferase assay. Studies very useful tools for pharmacological investigations. have indicated that the human H2 receptor gene [3H]-mepyramine is, for example, successfully used resides on chromosome 5.30 Interestingly, several 24 as an H1 receptor radioligand. These so-called polymorphisms have been found in the human H2 classical ‘antihistamines’ easily penetrate the brain receptor gene33 and one of the mutations has been 2 34 and are therefore also useful in in vivo CNS studies. linked to schizophrenia. The histamine H2 receptor Elimination of the blood-brain-barrier passage by is coupled to the adenylate cyclase system in a some minor structural modifications has resulted variety of tissues (e.g. brain, stomach, heart, gastric Figure 1 | Chemical structures of selected H receptor ligands 1 H N NH2 N NH2 HN N N S 2-Thiazolylethylamine Histamine N NH2 Br 2-Pyridylethylamine NH2 (endogenous ligand) 2-(3-Bromophenyl) histamine Cl O CO2H MeO N NMe2 N N N N CO2H H Cetirizine Mepyramine OH N N Cl H Me N N HO Fexofenadine Triprolidine N N N Loratidine O Astemizole N O OEt F (Bold Text Denotes Compounds Available From Tocris) | Histamine Receptors Figure 2 | Chemical structures of selected H2 receptor ligands NH Me 2 NH N N S Me2N S NH N N N H2N S NH2 HN H H H Dimaprit N Amthamine H H Impromidine H H H H N N N O N N N N NHMe S Me S N N N S N NC Ranitidine NO2 Burimamide H Me Cimetidine NH2 NH2 H H N N N N S N S Me S N H2N S N O N N SO2NH2 N H2N H S NC N Famotidine Zolantidine Tiotidine H2N (Bold Text Denotes Compounds Available From Tocris) mucosa, lung).24 Moreover, cell lines transfected for the development of selective and clinically useful 45,47,48 with the cloned H2 receptor genes showed an H2 receptor antagonists, such as cimetidine. The 35,36,37 H2 receptor-mediated increase of cAMP. In 4-methylimidazole