HISTAMINE RECEPTORS

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of new compounds (e.g. burimamide, cimetidine),which were able to block the effects of histamineon the stomach and the heart. These H2receptorantagonists proved to be very useful in the therapyof gastric ulcers. In recent years it becameapparent that histamine also functions as aneurotransmitter. 1 As with many otherneurotransmitter systems, a presynaptic receptorfor histamine (H ) exists as well. 53This receptorsubtype regulates the release and synthesis ofhistamine (autoreceptor), but is also involved inthe regulation of the release of many otherimportant neurotransmitters, such asnoradrenaline, dopamine, serotonin andacetylcholine (heteroreceptor). 7Selective Ligands for the Three HistamineReceptor SubtypesFor all three receptor subtypes selective agonistsand antagonists are available.H1ReceptorsModification of the imidazole moiety of histaminehas been the most successful approach forobtaining selective H1agonists (figure 1). Thepresence of the tautomeric N-Nsystem of theimidazole ring is not obligatory, as reflected by theselective H1agonists 2-pyridylethylamine and 2-thiazolylethylamine. Substitution of the imidazolering at the 2-position leads to relatively selectiveH1agonists. For example, 2-( meta-halogenated)phenylhistamines are relatively potent H1receptoragonists at the guinea-pig ileum; 8 however, thesecompounds act as partial agonists in othersystems. 9 A wide array of potent and selective H1antagonists are available. 6 Compounds such asmepyramine (also called pyrilamine) andtriprolidine (figure 1) are highly potent H1antagonists and very useful tools forpharmacological investigations. [ 3H]-mepyramineis, for example, successfully used as an H1receptor radioligand.10These so-called classical“antihistamines” easily penetrate the brain andare therefore also useful in in vivo studies.Clinically, the CNS penetration of these drugscauses sedation. Elimination of the blood-brainbarrierpassage by some minor structuralmodifications (figure 1) has resulted in many new,non-sedating H1antagonists (e.g. cetirizine,astemizole or loratadine), that are currentlysuccessfully marketed to treat allergicconditions. 6H2ReceptorsThe first selective H2receptor agonist, dimaprit,was found during a search for H2receptorantagonists in a series of isothiourea derivatives.Dimaprit is a relatively selective H2receptoragonist; it is almost as active as histamine at theH2 receptor, but hardly displays any H1receptoragonism11and is a moderate H3receptorantagonist. 12 Recently, amthamine (2-amino-5-(2-aminoethyl)-4-methylthiazole), a rigid dimapritanalog (figure 2), has been developed. Thiscompound combines a high H2receptor selectivitywith a potency which is slightly higher comparedto histamine, both in vitro and in vivo. 13, 14 An H2receptor agonist that is also more potent thanhistamine is the guanidine derivative impromidine(figure 2). This ligand actually combines a ratherhigh H2receptor affinity with a reduced efficacy.Impromidine also shows moderate and potentantagonistic activity at the H1- and the H3receptorrespectively. 5, 15The finding that N-guanylhistamine acts as apartial H2agonist in a gastric acid secretion testled to the development of the relatively weak H2antagonist burimamide (figure 2), which was agood lead for the development of clinically usefulH receptor antagonists. 42Subsequently, manycompounds with H2receptor antagonisticproperties, such as cimetidine, have beenFigure 2. Chemical structures of some H receptor agonists and antagonists2Me 2 N S NHDimapritNH 2H 2 NCH 3NSNH 2AmthamineHNNNHNHNHImpromidineSMeHNNNNHHNHNSCH 3CH 3 NCNCimetidineHNNBurimamideHNSHNMeNH 2 NH 2 N N SOMe 2 NSSTiotidineHNNCHNNHNHNMeMeSNNHOZolantidineNH 2 NH 2 NNSNSFamotidineHN NH 2NSO 2 NH 2RanitidineO 2 N(bold text denotes compounds available from Tocris)2
developed.16, 17Most of these H2blockers can beconsidered as having small variations on ageneral structure. The 4-methylimidazole moietyof cimetidine can easily be replaced by otherheterocyclic groups (figure 2). Replacement by asubstituted furan- (e.g. ranitidine) or thiazole ring(e.g. tiotidine and famotidine) leads to compoundsthat are usually more potent at the H2receptorcompared to cimetidine. Moreover, thereplacement of the imidazole moiety alsoeliminates the undesired inhibition of cytochromeP-450. 17 The potent H2antagonists tiotidine andiodoaminopotentidine are successfully used astritiated and iodinated radioligands for the H2receptor respectively. 10 The newly developedbrain-penetrating H2antagonist zolantidine is animportant tool for in vivo CNS studies. 18Very recently, the H2receptor was reported to bespontaneously active in transfected CHO cells. 19Based on this concept, the H2antagonists werereclassified; cimetidine, ranitidine and famotidineare in fact inverse agonists, whereas burimamideacts in this model system as a neutralantagonist. 19H3ReceptorsAt the histamine H3receptor, histamine itself is ahighly active agonist. Mono- or dimethylation ofthe terminal amino function results in compoundsthat are more active and H3selective with regardto H1 and H2receptors, than histamine.Methylation of the -carbon atom of theethylamine sidechain drastically increases thepotency at the H3receptor. This increased activityresides completely in the R-isomer; thecorresponding S-isomer is approximately 100-fold less potent. Since the methylation leads tohighly reduced activity at both the H1- and H2receptor, R-( )-methylhistamine (figure 3) is avery selective agonist at the H3receptor. Incombination with its less active S-isomer, thiscompound has proven to be highly useful for thepharmacological characterisation of H3receptormediatedeffects.12Tritiated forms of N-methylhistamine and R-( )-methylhistamine arecurrently available as radiolabelled agonists forthe H receptor. 123For potent H3agonism, theamine function of histamine can be replaced by anisothiourea group, as in imetit (figure 3). Imetit isalso very active in vitro and in vivo, 20-22as is R-( )-methylhistamine. The amine function can also beincorporated in ring structures to producecompounds such as immepip (figure 3). Thiscompound again, is effective in vitro and in vivo.23Moreover, whereas R-( )-methylhistamine showssome H1 and 2agonistic activity and imetit actsas a 5-HT3agonist, 24-26 immepip is devoid ofthese activities. 25Various H2receptor selective agents are alsorather potent H receptor antagonists. 53Themoderately active H2antagonist burimamide (pA2= 5.1) is an effective H3antagonist (pA 2= 7.2), andsome H2agonists (impromidine and dimaprit) arealso active as H receptor antagonists. 53Thedistinct pharmacology of the H3receptor wasconfirmed by the development of the prototypic H3receptor antagonist thioperamide (figure 3). 27This compound is active in various in vitro H3receptor assays but shows some 5-HT3receptorantagonism. 26 Thioperamide penetrates the CNSand has been used in several in vivo studies.Based on the H3receptor agonist imetit, the highlypotent antagonists clobenpropit (figure 3) andiodophenpropit were developed. 22 Thesecompounds also show some 5-HT3receptorantagonism26and do not readily penetrate theCNS. 28 Recently, a variety of other potent H3receptor antagonists have been described,including impentamine, GT2016 andiodoproxyfan (figure 3). 29 Consequently, variousantagonists have been described as radioligandsfor the H3receptor (e.g. [ 125I]-iodophenpropit and[ 125I]-iodoproxyfan).30, 31Figure 3. Chemical structures of some H receptor agonists and antagonists3NNHMeNH 2NNHImetitSNH 2NHHNNOIodoproxyfanIR-( )-MethylhistamineHNNNHNSHNNImmepipNHNNHS NHClThioperamideNHClobenpropitOHNNNGT 2016HNNImpentamineNH 2(bold text denotes compounds available from Tocris)3
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Page 6: Histaminergics Available from Tocri

HISTAMINE RECEPTORS

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