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Home , Amthamine, Histamine receptor, Immepip, Impromidine, Iodophenpropit

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 of the 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 , 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 “” (e.g. ), 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. 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

F

OCO2H NH2 N

OOEt HN N N N N H Cl N Br N Cl 2-(3-Bromophenyl)histamine H3C

(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. , ), 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 .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 (), 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, , 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, (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 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 N S N O H H H2N N N NNH2 S

H2N S 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 (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 (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 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 (figure 3).27 H3 Receptors This compound is active in variousin vitro H3 At the , 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 (figure 3) and Methylation of thea -carbon atom of the were developed.22 These ethylamine sidechain drastically increases the compounds also show some 5-HT3 receptor potency at the H3 receptor. This increased activity antagonism26 and do not readily penetrate the resides completely in the R-isomer; the 28 CNS. Recently, a variety of other potent H3 corresponding S-isomer is approximately 100- receptor antagonists have been described, fold less potent. Since the methylation leads to including , GT2016 and highly reduced activity at both the H12 - and H iodoproxyfan (figure 3).29 Consequently, various receptor, R-(a )-methylhistamine (figure 3) is a antagonists have been described as radioligands very selective agonist at the H receptor. In 125 3 for the H3 receptor (e.g. [ I]-iodophenpropit and combination with its less active S-isomer, this [125 I]-iodoproxyfan). 30, 31 compound has proven to be highly useful for the

Figure 3. Chemical structures of some H3 receptor agonists and antagonists

NH SNH 2 N N O NH HN Me 2 N N N Imetit I H H Iodoproxyfan R-(a )-Methylhistamine

HN N HN N NH NH N HN Immepip S N SN H Thioperamide N Cl H Clobenpropit

O

N NH2 HN N HN Impentamine GT 2016 N

(bold text denotes compounds available from Tocris)

3 Molecular Biology of Histamine Receptors concentration following H1 receptor stimulation can explain a variety of cellular responses, such Both the histamine H12 and H receptor belong to as nitric oxide production, cAMP and cGMP the large family of G-protein coupled receptors accumulation and phospholipase A2 and 10 (GPCRs). The cDNA encoding a bovine H1 phospholipase D activation. Yet, studies with G- receptor protein was cloned in 1991 after an protein toxins and in calcium-free medium expression cloning strategy in Xenopus indicate that both the H1 receptor-mediated 32 oocytes. The deduced amino acid sequence activation of phospholipase A2 and cAMP revealed a 491 amino acid protein of 56 kDa. elevation are also mediated by an unknown, Using the cDNA sequence encoding the bovine secondary mechanism (G-protein mediated?). H1 receptor, the cDNA sequences and intronless 33 34, 35 genes encoding the rat, guinea-pig, The is coupled to the 36-39 40 human and mouse H1 receptor proteins adenylate cyclase system in a variety of tissues were cloned soon thereafter. The proteins are (e.g. brain, stomach, heart, gastric mucosa, slightly different in length, highly homologous and lung).10 Moreover, cell lines transfected with the do not show major differences in pharmacology. cloned H22 receptor genes showed an H receptor- Analysis of the 5¢ -flanking region of the human, rat mediated increase of cAMP.50-52 Although 33, 34, 36 and guinea-pig gene resulted in the coupling of the H2 receptor to adenylate cyclase is identification of several DNA-binding motifs, well accepted, some findings argue against a including potential glucocorticoid responsive universal role of cAMP. New signalling pathways elements. The human H1 receptor gene resides have recently been described for the H2 receptor. on chromosome 3.41 In differentiated HL-60 cells and CHO or HEPA cells transfected with the H22 receptor cDNA, an H Gantzet al 42 were the first to clone a cDNA receptor-mediated increase of the intracellular 2+ encoding a 359 amino acid H2 receptor. Using Ca concentration and/or IP3 levels was degenerate primers based on the known observed.52-56 Moreover, in CHO cells expressing sequence similarity of various GPCRs, the H2 the rat H22 receptor, activation of the H receptor receptor sequence was obtained from canine resulted in an inhibition of the release of gastric parietal cDNA by PCR. Soon thereafter, arachidonic acid induced by either constitutive the intronless genes encoding the rat,43 human, 44 purinergic receptors or a Ca2+ -ionophore, 51 as 45 46 guinea-pig and mouse H2 receptor were well as an increase in cAMP. These new signal cloned by means of homology screening. As for transduction pathways are both regulated via the H1 receptor, the receptor proteins are slightly unknown, cAMP-independent pathways. different in length, but do not show major pharmacological differences. Identification of the The H3 receptor is also thought to belong to the promotor region of the human H2 receptor gene superfamily of G-protein coupled receptors. From revealed the existence of regulatory transcription both functional and binding studies an interaction sites and regions displaying stimulatory and with a G-protein is suggested.10 The concept of G- inhibitory effects on gene expression monitored in protein involvement is further strengthened by a a luciferase assay.47 Recent studies have recent study57 showing a pertussis toxin sensitive 35 indicated that the human H2 receptor gene resides stimulation of [ S]-GTPg S binding in rat cortical on chromosome 5.45 Interestingly, several membranes. At present, almost nothing is known polymorphisms have been found in the human H2 about the intracellular biochemical pathways that 48 receptor gene and one of the mutations has are stimulated via the H3 -receptor. Several 49 been linked to schizophrenia. studies failed to show a coupling of H3 receptors to intracellular cAMP levels;10 a not completely Although the genetic information for the H12 and H understood, negative coupling to phospholipase receptor has been available for some years now, C was shown in HGT-1 gastric tumor cells.58 A as yet no information on the primary structure of coupling to N-type Ca2+ -channels, as shown for the H3 receptor is known. other presynaptic receptors, has been reported in functional studies with heart and duodenal Signal Transduction of the Histamine preparations.59, 60 The biochemical basis for this Receptors coupling is also, as yet, unknown.

The is associated with the Further Directions -catalyzed formation of inositol 1,4,5-triphosphate (IP3 ) and 1,2-diacylglycerol Many new developments are awaited, particularly (DAG). Histamine induces production of inositol in the field of the H3 receptor where both the phosphates in several tissues (including brain, primary receptor structure and the signal airway, intestinal and vascular smooth muscle10 ) transduction pathway(s) are, as yet, unknown. via a pertussis toxin-insensitive G-protein. However, new developments are expected in the Although the G-protein probably belongs to the next five years. For the H12 and H receptors, Gaaq11 /G family, the actual nature of the pertussin availability of the cDNAs will provide new insights toxin-insensitive G-protein remains unclear. Since on structure-function relationships of the receptor Ca2+ is involved in the regulation of many cellular protein, receptor regulation, and gene expression, functions, the increase of the intracellular Ca2+ in the years to come.

4 References 31.Jansen et al (1994) Characterization of the binding of the first selective radiolabelled histamine H3 receptor antagonist, 1.Schwartz et al (1991) transmission in [125 I]-iodophenpropit, to rat brain. Br.J.Pharmacol.113 355. mammalian brain. Physiol.Rev.71 1. 32.Yamashita et al (1991) Expression cloning of a cDNA 2.Ring et al (1985) Histamine and allergic deseases. In New encoding the bovine histamine H1 receptor. Trends in Allergy. Ed. J. Ring, pp 44, Springer-Verlag, Berlin. Proc.Natl.Acad.Sci.USA.88 11515. 3.Ash and Schild (1966) Receptors mediating some actions of 33.Fujimoto et al (1993) Genomic cloning of the rat histamine histamine. Br.J.Pharmacol.27 427. H1 receptor. Biochem.Biophys.Res.Comm.190 294. 4.Black et al (1972) Definition and antagonism of histamine H2 34.Horio et al (1993) Molecular cloning of the guinea-pig receptors. Nature236 385. histamine H receptor gene. J.Biochem.114 408. 5.Arrang et al (1983) Auto-inhibition of brain histamine release 1 35.Traiffort et al (1994) Guinea-pig histamine H1 receptor. I. mediated by a novel class (H3 ) of histamine receptors. Gene cloning, characterization, and tissue expression Nature302 832. revealed by in situ hybridization. J.Neurochem.62 507. 6.Zhang et al (1997) Histamine H1 -receptor antagonists. In 36.Fukui et al (1994) Molecular cloning of the human histamine Burger’s Medicinal Chemistry and Drug Discovery, Fifth H1 receptor gene. Biochem.Biophys.Res.Comm.201 894. Edition. Ed. M. E. Wolff, pp 495. John Wiley & Sons, Inc. 37.De Backer et al (1993) Genomic cloning, heterologous 7.Schlicker et al (1994) Modulation of neurotransmitter release expression and pharmacological characterization of a human via histamine H heteroreceptors. Fundam.Clin.Pharmacol. 8 3 histamine H1 receptor. Biochem.Biophys.Res.Comm. 197 128. 1601. 8.Zingel et al (1995) Developments in histamine H -receptor 1 38.Moguilevsky et al (1994) Stable expression of human H1 - agonists. In Progress in Drug Research, Ed. E. Jucker, pp histamine-receptor cDNA in Chinese hamster ovary cells - 49. Birkhauser Verlag, Basel (Switzerland). Pharmacological characterisation of the protein, tissue 9.Leurs et al (1994) Site-directed mutagenesis of the distribution of messenger RNA and chromosomal localisation histamine H1 receptor reveals a selective interaction of of the gene. Eur.J.Biochem.224 489. asparagine207 with subclasses of H receptor agonists. 1 39.Smit et al (1996) Regulation of the human histamine H1 Biochem.Biophys.Res.Comm.201 295. receptor stably expressed in Chinese hamster ovary cells. 10.Leurs et al (1995) Molecular pharmacological aspects of Br.J.Pharmacol.117 1071. histamine receptors. Pharmacol.Ther.66 413. 40.Inoue et al (1996) Characteristics of the mouse genomic 11.Parsons et al (1977) Dimaprit -[S-[3(N,N- histamine H1 receptor gene. Genomics36 178. dimethylamino)propyl]isothiourea]- A highly specific 41.Leconiat et al (1994) Chromosomal localization of the histamine H receptor agonist. Agents Actions7 31. 2 human histamine H1 -receptor gene. Hum.Genet.94 186. 12.Leurs et al (1995) The medicinal chemistry and therapeutic 42.Gantz et al (1991) Molecular cloning of a gene encoding the potential of ligands for the histamine H receptor. In 3 histamine H2 receptor. Proc.Natl.Acad.Sci.USA.88 429. Prog.Drug Res. Ed. E. Jucker, pp 107. Birkhauser Verlag, 43.Ruat et al (1991) Cloning and tissue expression of a rat Basel (Switzerland). histamine H2 receptor gene. Biochem.Biophys.Res.Comm. 13.Eriks et al (1992) Histamine H2 -receptor agonists - 179 1470. synthesis, in vitro pharmacology, and qualitative structure- 44.Gantz et al (1991) Molecular cloning of the human histamine activity relationships of substituted 4-(2-Aminoethyl)thiazoles H receptor. Biochem.Biophys.Res.Comm.178 1386. and 5-(2-Aminoethyl)thiazoles. J.Med.Chem.35 3239. 2 45.Traiffort et al (1995) The guinea-pig histamine H2 receptor: 14.Coruzzi et al (1996) Cardiovascular effects of the novel Gene cloning, tissue expression and chromosomal histamine H2 receptor agonist amthamine: Interaction with localization of its human counterpart. the adrenergic system. Arch.Pharmacol.353 417. Biochem.Biophys.Res.Comm.211 570. 15.Durant et al (1978) Impromidine (SK&F 92676) is a very 46.Kobayashi et al (1996) Cloning, RNA expression and potent and specific agonist for histamine H receptors. 2 chromosomal location of a mouse histamine H2 receptor Nature276 403. gene. Genomics37 390. 16.Ganellin (1992) Pharmacochemistry of H12 and H receptors. 47.Nishi et al (1995) Identification of the promoter region of the In The Histamine Receptor. Ed. J. C. Schwartz and H. Haas, human histamine H2 -receptor gene. pp 1. Wiley-Liss, New York. Biochem.Biophys.Res.Comm.210 616. 17.Van der Goot et al (1991) Structural requirements for 48.Orange et al (1996) Allelic variations of the human histamine histamine H agonists and H antagonists. In Handbook of 22 H2 receptor gene. Neuroreport7 1293. Experimental Pharmacology. Ed. B. Uvnas, pp 573. Springer- 49.Orange et al (1996) Individuals with schizophrenia have an Verlag, Berlin. increased incidence of the H R(649G) allele for the histamine 18.Young et al (1988) Development of a new physiochemical 2 H2 receptor gene. Mol.Psychiatr.1 466. model for brain penetration and its application to the design 50.Leurs et al (1994) Pharmacological characterization of the of centrally acting H receptor histamine antagonists. 2 human histamine H2 receptor stably expressed in Chinese J.Med.Chem.31 626. hamster ovary cells. Br.J.Pharmacol.112 847. 19.Smit et al (1996) Inverse agonism of histamine H 2 51.Traiffort et al (1992) Expression of a cloned rat histamine H2 antagonists accounts for upregulation of spontaneously receptor mediating inhibition of arachidonate release and active histamine H2 receptors. Proc.Natl.Acad.Sci.USA. 93 activation of cAMP accumulation. Proc.Natl.Acad.Sci.USA. 6802. 89 2649. 20.Garbarg et al (1992) S-[2-(4-Imidazolyl)ethyl]isothiourea, a 52.Delvalle et al (1992) Characterization of H2 receptor: linkage highly specific and potent histamine H receptor agonist. 2+ 3 to both adenylyl cyclase and [Ca ]i signalling systems. J.Pharmacol.Exp.Ther.263 304. Am.J.Physiol.263 G967. 21.Howson et al (1992) Two novel, potent and selective 53.Gespach et al (1982) Identification and characterization of histamine H3 receptor agonists. Bioorg.Med.Chem.Lett.2 77. surface receptors for histamine in the human promyelocytic 22.Van der Goot et al (1992) Isothiourea analogues of leukemia cell line HL-60. Mol.Pharmacol.22 547. histamine as potent agonists or antagonists of the histamine 54.Mitsuhashi et al (1989) Multiple signalling pathways of H3 -receptor. Eur.J.Med.Chem.27 511. histamine H receptors. J.Biol.Chem.264 18356. 23.Vollinga et al (1994) A new potent and selective histamine 2 55.Burde and Seifert (1996) Stimulation of histamine H2 - H3 receptor agonist, 4-(1H-imidazol-4-ylmethyl)piperidine. receptors activates Ca2+ influx in all-trans-retinoic acid- J.Med.Chem.37 332. differentiated HL-60 cells independently of phospholipase C 24.Hey et al (1992) (R)-a -methylhistamine augments neural, or adenylyl cyclase. Arch.Pharmacol.353 123. cholinergic bronchospasm in guinea-pig by histamine H1 56.Seifert et al (1992) Histamine increases cytosolic Ca2+ in receptor activation. Eur.J.Pharmacol.211 421. dibutyryl-cAMP-differentiated HL-60 cells via H1 receptors 25.Coruzzi, G. et al (1995) Cardiovascular effects of selective and is an incomplete secretagogue. Mol.Pharmacol.42 227. agonists and antagonists of histamine H receptors in the 3 57.Clark and Hill (1996) Sensitivity of histamine H3 receptor anaesthetised rat. Arch.Pharmacol.351 569. agonist-stimulated [35 S]GTPg S binding to pertussis toxin. 26.Leurs et al (1995) Evaluation of the receptor selectivity of the Eur.J.Pharmacol.296 223. H receptor antagonists, iodophenpropit and thioperamide: 3 58.Cherifi et al (1992) Purification of a histamine H3 receptor an interaction with the 5HT3 receptor revealed. negatively coupled to phosphoinositide turnover in the human Br.J.Pharmacol.116 2315. gastric cell line HGT-1. J.Biol.Chem.267 25315. 27.Arrang et al (1987) Highly potent and selective ligands for 59.Poli et al (1994) Signal transducing mechanisms coupled to histamine H3 receptors. Nature327 117. histamine H32 receptors anda adrenoceptors in the guinea- 28.Mochizuki et al (1996) Brain penetration of the histamine H3 pig duodenum: Possible involvement of N-type Ca++ receptor antagonists thioperamide and clobenpropit in rat 125 channels. J.Pharmacol.Exp.Ther.270 788. and mouse, determined withex vivo [ I]iodophenpropit 60.Endou et al (1994) Histamine H -receptor signalling in the binding. Brain Res.743 178. 3 heart: Possible involvement of Gio /G proteins and N-type 29.Stark et al (1996) Development of histamine H3 -antagonists. Ca++ channels. J.Pharmacol.Exp.Ther.269 221. Drugs Future.21 507. 30.Ligneau et al (1994) [125 I]Iodoproxyfan, a new antagonist to label and visualize cerebral histamine H3 receptors. J.Pharmacol.Exp.Ther.271 452.

5 Available from Tocris

H1 Receptor

Agonists

0646 HTMT ...... H1 agonist

Antagonists

0784 ...... 0660 Mepyramine...... Standard selective H1 antagonist 0587 2-[4-(2-Methylethyl)phenyl]-3-[3-(N,N-...... H1 antagonist dimethylamino)propyl]-1,3-thiazolidin-4-one

0662trans -Triprolidine...... Standard H1 antagonist, highly potent

H2 Receptor

Agonists

0668 Amthamine ...... Highly selective standard H2 agonist 0506 Dimaprit ...... Standard H2 selective agonist

Antagonists

0902 Cimetidine ...... H21 antagonist, I agonist 0833 ICI-162,846...... Potent H2 antagonist, active in vivo 0826 Tiotidine ...... Potent, selective H2 antagonist 1070 Zolantidine...... Potent, centrally active H2 antagonist

H3 Receptor

Agonists

0729 Imetit...... Standard selective H3 agonist 0932 Immepip...... Standard H3 agonist a 0573 N -Methylhistamine ...... Non-selective H3 agonist 0569 R(-)-a -Methylhistamine...... Potent and selective standard H3 agonist 0572 S(+)-a -Methylhistamine...... H3 agonist, less active enantiomer

Antagonists

0752 Clobenpropit ...... Highly potent, selective H3 antagonist 0779 Iodophenpropit ...... Very potent and selective standard H3 antagonist 0644 Thioperamide ...... H3 antagonist, active in vivo Histaminergics - Other

0743 DPPE...... Inhibitor of histamine binding at the intracellular binding site 0512 SKF 91488 ...... Histamine N-methyl transferase inhibitor

Histamine Receptors, Tocris Reviews No. 6, October 1997, reprinted February 2000

Published and distributed by Tocris Cookson

Editor: Samantha Manley, Ph.D. Managing Editor: Duncan Crawford, Ph.D. Design and Production: Jane Champness; Lacia Ashman, MA

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