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Histamine Receptors Tocris Scientific Review Series Tocri-lu-2945 Histamine Receptors Iwan de Esch and Rob Leurs Introduction Leiden/Amsterdam Center for Drug Research (LACDR), Division Histamine is one of the aminergic neurotransmitters and plays of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit an important role in the regulation of several (patho)physiological Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The processes. In the mammalian brain histamine is synthesised in Netherlands restricted populations of neurons that are located in the tuberomammillary nucleus of the posterior hypothalamus.1 Dr. Iwan de Esch is an assistant professor and Prof. Rob Leurs is These neurons project diffusely to most cerebral areas and have full professor and head of the Division of Medicinal Chemistry of been implicated in several brain functions (e.g. sleep/ the Leiden/Amsterdam Center of Drug Research (LACDR), VU wakefulness, hormonal secretion, cardiovascular control, University Amsterdam, The Netherlands. Since the seventies, thermoregulation, food intake, and memory formation).2 In histamine receptor research has been one of the traditional peripheral tissues, histamine is stored in mast cells, eosinophils, themes of the division. Molecular understanding of ligand- basophils, enterochromaffin cells and probably also in some receptor interaction is obtained by combining pharmacology specific neurons. Mast cell histamine plays an important role in (signal transduction, proliferation), molecular biology, receptor the pathogenesis of various allergic conditions. After mast cell modelling and the synthesis and identification of new ligands. degranulation, release of histamine leads to various well-known symptoms of allergic conditions in the skin and the airway system. In 1937, Bovet and Staub discovered compounds that antagonise the effect of histamine on these allergic reactions.3 Ever since, there has been intense research devoted towards finding novel ligands with (anti-) histaminergic activity. This research field has been fuelled by the consecutive discovery of four unique histamine receptor subtypes. Every receptor subtype has a very distinct (patho)physiological role and all of them belong to the superfamily of G-protein-coupled receptors (GPCRs). The histamine H1 and H2 receptor subtypes have proven to be excellent drug targets. Ligands for the histamine H3 receptor subtype are currently entering clinical studies and the recently discovered histamine H4 receptor subtype is subject of intense preclinical research. The Histamine H1 Receptor Until the seventies, histamine research focused on the role of histamine in allergic diseases. This resulted in the development of several potent ‘antihistamines’ (e.g. mepyramine, see figure 1), which were useful in inhibiting pronounced symptoms of allergic Contents 4 conditions. However, the first generation of 1H receptor Introduction ............................................................................................. 1 antagonists that were developed for treating allergies revealed The Histamine H1 Receptor ................................................................... 1 distinct side effects such as sedation. This particular physiological effect of the ligands was eliminated by structural modifications Ligands for H1 Receptors .................................................................. 2 that prevent blood-brain-barrier penetration of the drugs. The The Histamine H Receptor ................................................................... 3 2 first generation as well as the more recently developed Ligands for H Receptors .................................................................. 3 2 antihistamines (originally termed antagonists but later 5 The Histamine H3 Receptor ................................................................... 4 reclassified as inverse agonists ) are clinically very successful and are widely available drugs. In 1991, the cDNA encoding a Ligands for H3 Receptors .................................................................. 4 bovine H receptor protein was cloned after an expression cloning The Histamine H Receptor ................................................................... 6 1 4 strategy in Xenopus oocytes.6 The deduced amino acid sequence Ligands for H Receptors .................................................................. 7 4 revealed a 491 amino acid protein of 56 kDa. Using the cDNA Conclusion ...................................................................................................7 sequence encoding the bovine H1 receptor, the cDNA sequences 3,7 8,9 10,11 References ..................................................................................................8 and intronless genes encoding the rat, guinea-pig, human and mouse12 H receptor proteins were cloned soon thereafter. Histamine Receptor Compounds .............................................................9 1 tocris.com | 1 Tocris Scientific Review Series These receptor proteins are slightly different in length, highly binding site elucidation18), biophysical approaches (such as solid- homologous and do not show major pharmacological differences. state NMR19) and investigations towards the general activation Analysis of the 5′-flanking region of the human, rat and guinea- mechanisms of GPCRs.20,21 pig gene7,8,10 resulted in the identification of several DNA-binding motifs, including potential glucocorticoid responsive elements. Ligands for H1 Receptors The human H receptor gene resides on chromosome 3.13 The H 1 1 Modification of the imidazole moiety of histamine has been the receptor belongs to the large family of GPCRs. The receptor is most successful approach for obtaining selective H agonists associated with the phospholipase C-catalysed formation of 1 (figure 1). The presence of the tautomeric Nπ-Nτ system of the inositol 1,4,5-triphosphate (IP ) and 1,2-diaylglycerol (DAG). 3 imidazole ring is not obligatory, as reflected by the selective H Histamine induces production of inositol phosphates in several 1 agonists 2-pyridylethylamine and 2-thiazolylethylamine. Substi- tissues (including brain, airway, intestinal and vascular smooth tution of the imidazole ring at the 2-position leads to relatively muscle24) via G protein activation.14 In other tissues, activation αq selective H agonists. For example, 2-(meta-halogenated) of H receptors can also stimulate adenylyl cyclase and formation 1 1 phenylhistamines are relatively potent H receptor agonists at of cAMP. Not all details of this signalling pathway are understood, 1 the guinea-pig ileum;22 however, these compounds act as partial for example questions remain about the G protein and the agonists in other systems.23 A wide array of potent and selective involvement of Ca2+.15 In any case, alternative signalling pathways H antagonists are available.4 Compounds such as mepyramine can be mediated by the histamine H receptor. Recent results 1 1 (also called pyrilamine) and triprolidine are highly potent H indicate that the functional heterogeneity can be ligand- 1 antagonists and very useful tools for pharmacological directed.16 investigations. [3H]-mepyramine is, for example, successfully used as an H receptor radioligand.24 These so-called classical The histamine H1 receptor is a well established drug target and 1 ‘antihistamines’ easily penetrate the brain and are therefore also has been thoroughly studied for decades. Nevertheless, H1 receptor research continues to flourish as many new techniques useful in in vivo CNS studies.2 Elimination of the blood-brain- and approaches are being developed by using this receptor as an barrier passage by some minor structural modifications has archetypal GPCR target. Most notably, in the last few years, the resulted in many new, non-sedating H1 antagonists (e.g., cetirizine, astemizole, fexofenadine and loratidine).4 histamine H1 receptor has been the subject of various molecular biology studies (e.g., large-scale overproduction17 and GPCR Figure 1 | Chemical structures of selected H receptor ligands 1 H N NH N NH2 N 2 HN Br N NH S N 2 NH2 Histamine 2-Pyridylethylamine 2-Thiazolylethylamine 2-(3-Bromophenyl) (endogenous ligand) histamine N Cl O CO2H N H MeO N NMe2 N N N Me Mepyramine Triprolidine Cetirizine H Cl N N CO H N 2 N N OH O N N O OEt F HO Astemizole Loratidine Fexofenadine (Bold text denotes compounds available from Tocris at time of publication.) 2 | tocris.com Histamine Receptors Figure 2 | Chemical structures of selected H2 receptor ligands Me NH N N S N N N HN H H H H2N N S NH2 Dimaprit Amthamine Impromidine H H H H N N N O N N S Me S N N N NC NO2 H Me Cimetidine Ranitidine NH2 NH2 H H S N N N N S S Me H2N N SO2NH2 N N H2N N N N S NC S N O H2N H Tiotidine Famotidine Zolantidine (Bold text denotes compounds available from Tocris at time of publication.) 38,39 was observed. Moreover, in CHO cells expressing the rat H2 The Histamine H2 Receptor receptor, activation of the H2 receptor resulted in an inhibition of The observation that the classical ‘antihistamines’ (i.e. H1 the release of arachidonic acid induced by either constitutive receptor inverse agonists) cannot antagonise all histamine- purinergic receptors or a Ca2+-ionophore,36 as well as an increase induced effects (e.g. at the stomach and the heart), led Ash and in cAMP. These new signal transduction pathways are both Schild in 1966 to propose two distinct subtypes of histamine regulated via unknown, cAMP-independent pathways. 25 receptors: H1 and H2. This hypothesis became generally
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