HISTAMINE RECEPTORS Rob Leurs and Henk Timmerman Based on these observations histamine is Leiden/Amsterdam Centre for Drug Research considered as one of the most important Division of Medicinal Chemistry mediators of allergy and inflammation. Vrije Universiteit Amsterdam, The Netherlands Pharmacology of the Histamine Receptor Subtypes Introduction The advent of molecular biology techniques has greatly increased the number of Histamine is one of the aminergic pharmacologically distinct receptor subtypes in neurotransmitters, playing an important role in the the biogenic amine field, yet the pharmacological regulation of several (patho)physiological definition of the three distinct histamine receptor processes. In the mammalian brain histamine is subtypes by the pioneering work of Ash and synthesized in a restricted population of neurons Schild,34 Blacket al and Arrang et al 5 has still not located in the tuberomammillary nucleus of the been challenged by gene cloning approaches. posterior hypothalamus.1 These neurons project diffusely to most cerebral areas and have been Until the seventies, histamine research implicated in several brain functions (e.g. completely focused on the role of histamine in sleep/wakefulness, hormonal secretion, allergic diseases. This intensive research resulted cardiovascular control, thermoregulation, food in the development of several potent 1 intake, and memory formation). In peripheral “antihistamines” (e.g. mepyramine), which were tissues histamine is stored in mast cells, useful in inhibiting certain symptoms of allergic basophils, enterochromaffin cells and probably conditions.6 The observation that these also in some specific neurons. Mast cell histamine “antihistamines” did not antagonise all histamine- plays an important role in the pathogenesis of induced effects (e.g. at the stomach and the various allergic conditions. After mast cell heart), led Ash and Schild in 1966 to propose degranulation, release of histamine leads to 3 histamine H12 and H receptor subtypes. This various well-known symptoms of allergic hypothesis became generally accepted when 2 conditions in the skin and the airway system. Blacket al 4 succeeded in the synthesis of a series Figure 1. Chemical structures of some H1 receptor agonists and antagonists H N N MeO NMe2 S NH2 N N NN N OMe Mepyramine 2-Thiazolylethylamine Astemizole F OCO2H NH2 N OOEt HN N N N N H Cl N Br Cetirizine N Cl 2-(3-Bromophenyl)histamine H3C Loratadine Triprolidine (bold text denotes compounds available from Tocris) Tocris Cookson Ltd., UK Tocris Cookson Inc., USA Tel: + 44 (0)117 982 6551 Tel: (800) 421-3701 Fax: + 44 (0)117 982 6552 www.tocris.com Fax: (800) 483-1993 e-mail: [email protected] [email protected] e-mail: [email protected] of new compounds (e.g. burimamide, cimetidine), receptor radioligand.10 These so-called classical which were able to block the effects of histamine “antihistamines” easily penetrate the brain and on the stomach and the heart. These H2 receptor are therefore also useful inin vivo studies. antagonists proved to be very useful in the therapy Clinically, the CNS penetration of these drugs of gastric ulcers. In recent years it became causes sedation. Elimination of the blood-brain- apparent that histamine also functions as a barrier passage by some minor structural neurotransmitter.1 As with many other modifications (figure 1) has resulted in many new, neurotransmitter systems, a presynaptic receptor non-sedating H1 antagonists (e.g. cetirizine, 5 for histamine (H3 ) exists as well. This receptor astemizole or loratadine), that are currently subtype regulates the release and synthesis of successfully marketed to treat allergic histamine (autoreceptor), but is also involved in conditions.6 the regulation of the release of many other important neurotransmitters, such as H2 Receptors noradrenaline, dopamine, serotonin and The first selective H2 receptor agonist, dimaprit, 7 acetylcholine (heteroreceptor). was found during a search for H2 receptor antagonists in a series of isothiourea derivatives. Selective Ligands for the Three Histamine Dimaprit is a relatively selective H2 receptor Receptor Subtypes agonist; it is almost as active as histamine at the H21 receptor, but hardly displays any H receptor 11 For all three receptor subtypes selective agonists agonism and is a moderate H3 receptor and antagonists are available. antagonist.12 Recently, amthamine (2-amino-5- (2-aminoethyl)-4-methylthiazole), a rigid dimaprit H1 Receptors analog (figure 2), has been developed. This Modification of the imidazole moiety of histamine compound combines a high H2 receptor selectivity has been the most successful approach for with a potency which is slightly higher compared 13, 14 obtaining selective H1 agonists (figure 1). The to histamine, bothin vitro and in vivo. An H2 presence of the tautomeric Npt -N system of the receptor agonist that is also more potent than imidazole ring is not obligatory, as reflected by the histamine is the guanidine derivative impromidine selective H1 agonists 2-pyridylethylamine and 2- (figure 2). This ligand actually combines a rather thiazolylethylamine. Substitution of the imidazole high H2 receptor affinity with a reduced efficacy. ring at the 2-position leads to relatively selective Impromidine also shows moderate and potent H1 agonists. For example, 2-(meta -halogenated) antagonistic activity at the H13 - and the H receptor 5, 15 phenylhistamines are relatively potent H1 receptor respectively. agonists at the guinea-pig ileum;8 however, these compounds act as partial agonists in other The finding that Na -guanylhistamine acts as a 9 systems. A wide array of potent and selective H1 partial H2 agonist in a gastric acid secretion test 6 antagonists are available. Compounds such as led to the development of the relatively weak H2 mepyramine (also called pyrilamine) and antagonist burimamide (figure 2), which was a triprolidine (figure 1) are highly potent H1 good lead for the development of clinically useful 4 antagonists and very useful tools for H2 receptor antagonists. Subsequently, many 3 pharmacological investigations. [ H]-mepyramine compounds with H2 receptor antagonistic is, for example, successfully used as an H1 properties, such as cimetidine, have been Figure 2. Chemical structures of some H2 receptor agonists and antagonists NH NH 2 CH3 H S N N N N Me2NSNH HN H H N H2N NH N Dimaprit S 2 Impromidine Me Amthamine H H H H N N N N NH2 NS Me N S CH3 H H N N H NNS NC CH N N 2 N 3 NC Me Tiotidine H HN Cimetidine N S Burimamide H H O N N Me2NMeS N O2N Ranitidine N S N O H H H2N N N NNH2 Zolantidine S H2N S Famotidine N SO2NH2 (bold text denotes compounds available from Tocris) 2 16, 17 developed. Most of these H2 blockers can be pharmacological characterisation of H3 receptor- considered as having small variations on a mediated effects.12 Tritiated forms of Na - general structure. The 4-methylimidazole moiety methylhistamine and R-(a )-methylhistamine are of cimetidine can easily be replaced by other currently available as radiolabelled agonists for 12 heterocyclic groups (figure 2). Replacement by a the H3 receptor. For potent H3 agonism, the substituted furan- (e.g. ranitidine) or thiazole ring amine function of histamine can be replaced by an (e.g. tiotidine and famotidine) leads to compounds isothiourea group, as in imetit (figure 3). Imetit is that are usually more potent at the H2 receptor also very activein vitro and in vivo,20-22 as is R-(a )- compared to cimetidine. Moreover, the methylhistamine. The amine function can also be replacement of the imidazole moiety also incorporated in ring structures to produce eliminates the undesired inhibition of cytochrome compounds such as immepip (figure 3). This 17 P-450. The potent H2 antagonists tiotidine and compound again, is effectivein vitro and in vivo.23 iodoaminopotentidine are successfully used as Moreover, whereas R-(a )-methylhistamine shows tritiated and iodinated radioligands for the H2 some H anda agonistic activity and imetit acts 10 12 receptor respectively. The newly developed 24-26 as a 5-HT3 agonist, immepip is devoid of brain-penetrating H2 antagonist zolantidine is an these activities.25 important tool forin vivo CNS studies.18 Various H2 receptor selective agents are also Very recently, the H2 receptor was reported to be rather potent H receptor antagonists.5 The spontaneously active in transfected CHO cells.19 3 moderately active H22 antagonist burimamide (pA Based on this concept, the H2 antagonists were = 5.1) is an effective H antagonist (pA = 7.2), and reclassified; cimetidine, ranitidine and famotidine 32 some H2 agonists (impromidine and dimaprit) are are in fact inverse agonists, whereas burimamide 5 also active as H3 receptor antagonists. The acts in this model system as a neutral distinct pharmacology of the H receptor was antagonist.19 3 confirmed by the development of the prototypic H3 receptor antagonist thioperamide (figure 3).27 H3 Receptors This compound is active in variousin vitro H3 At the histamine H3 receptor, histamine itself is a receptor assays but shows some 5-HT3 receptor highly active agonist. Mono- or dimethylation of antagonism.26 Thioperamide penetrates the CNS the terminal amino function results in compounds and has been used in severalin vivo studies. that are more active and H3 selective with regard Based on the H3 receptor agonist imetit, the highly to H12 and H receptors, than histamine. potent antagonists clobenpropit (figure 3) and Methylation of thea