Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Session 2: Histamine Receptors: An Overview M. E. Parsons To cite this article: M. E. Parsons (1991) Session 2: Histamine Receptors: An Overview, Scandinavian Journal of Gastroenterology, 26:sup180, 46-52, DOI: 10.3109/00365529109093177 To link to this article: http://dx.doi.org/10.3109/00365529109093177
Published online: 08 Jul 2009.
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Histamine Receptors: An Overview M . E . PARSONS Smith Kline & French Research Ltd., Welwyn, Herts, U.K.
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Parsons ME. Histamine receptors: an overview. Scand J Gastroenterol1991,26(suppl 180), 46-52 Histamine is widely distributed throughout the body and has a broad range of pharmacologic effects. The advent of selective agonists and antagonists has allowed the identification and characterization of three types of histamine receptor. These same compounds have helped in our understanding of physiologic and pathologic roles for histamine. Clearly, histamine plays a central role in the physiologic control of gastric acid secretion. and this fact has led to the use of Hz antagonists such as cimetidine, and ranitidine is the therapy of acid-related diseases such as peptic ulcer. Histamine is also one of the prime mediators of a variety of allergic reactions, and H, antagonists play a therapeutic role in this context. However, despite the widespread distribution of histamine receptors in, for example, the central nervous, respiratory, cardiovascular, and immune systems, other physiologic roles for histamine have not been established. It is to be hoped that future research will alter this situation and possibly lead to other therapeutic indications for histamine agonists and antagonists.
Key words: Acid secretion; agonists; allergy; antagonists; histamine: H, receptors; H2 receptors; H3 receptors
M . E. Pursons, M.D., Smith Klirie & French Research Lld, The Frythe. Welwyn. H e m , AL6 9AR. U. K .
Receptors are the molecular sites where chemical messengers act. Their definition and classification require the availability of interacting ligandsthat is, agonists and antagonists-and. therefore, the major part of this chapter will address the development of these ligands. Histamine is widely distributed throughout the body and has a range of biologic actions. Many of these were first described in a series of papers by Dale & Laidlaw (1-3). Histamine was found to contract various smooth-muscle tissues from, for example, the respiratory and gastrointestinal tract and to cause a fall in blood pressure in experimental animals. Interestingly, the ability of histamine to stimulate gastric acid secretion was not established until 1920 by Popielski (4). ANTIHISTAMINES A possible pathologic role for histamine in various allergic and inflammatory disorders led to the
search for selective antagonists of the actions of histamine, and the first of these were the Fourneau antihistamines described by Bovet & Staub ( 5 ) . These compounds were found to antagonize the contractile effect of histamine on smooth muscle and to protect guinea-pigs against lethal doses of histamine causing bronchoconstriction. Subsequently, more potent histamine antagonists were synthesized, such as mepyrarnine (6) and diphenhydramine (7). Quantitative data obtained from studies on isolated smooth muscle by Halpern & Mauric (8) suggested that the mode of action at the receptor was competitive--that is, the antagonism they produced was surmountable-and in 1947 Schild (9) introduced PA, values to characterize antagonists. These antagonists were used to establish the criteria for comparing receptors in different tissues, and the establishment of similar pA2 values for a given antagonist in a range of tissues suggested receptor homogeneity.
Histamine Receptors
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THE IDENTIFICATION OF A SECOND CLASS OF HISTAMINE RECEPTORS With the advent of selective antihistamine drugs mapping of the distribution of histamine receptors could be performed. It became apparent at a relatively early stage, however, that even potent antagonists such as diphenhydramine failed to inhibit all the pharmacologic effects of histamine. Histamine produces a positive chronotropic effect on the isolated heart or atrium of most mammalian species, and this effect is not antagonized by classical antihistamines in concentrations that are sufficient to block selectively the histamine receptors on, for example, the guinea-pig ileum (10). Dews & Graham (11) showed that the effect of histamine in inhibiting the spontaneous or evoked contractions of the isolated rat uterus was completely refractory to antagonism by antihistaminic drugs. The inability of antihistamines to antagonize histamine-stimulated acid secretion was also established at an early stage (12). The first suggestion that histamine might produce responses by interaction with two receptor sites was made by Folkow et al. in 1948 (13). They found that in cats and dogs the fall in blood pressure induced by moderate doses of histamine could be reduced by diphenhydramine, but the responses to larger doses were refractory. It is interesting to note that this paper was published in the same year as Ahlquest first defined two adrenoceptors, the a and p adrenoceptor.
THE DEVELOPMENT OF HISTAMINE Hz-RECEPTOR ANTAGONIST In 1964 Black and his colleagues at Smith Kline and French started a research program directed towards establishing the existence of a second class of histamine receptors and to develop selected antagonists for this hypothecated receptor. Black drew an analogy with the adrenergic field (in which he had played a major role in the development of p receptor antagonists) and suggested that if a second class of histamine receptor existed, ligands to interact with it would be chemically closely related to histamine itself. Further evidence for receptor heterogeneity
47
was provided by the finding that simple methyl analogues of histamine showed different potencies relative to histamine depending on the assay system used (an analysis similar to that used by Ahlquest to establish adrenoceptor heterogeneity). Thus, 2-methylhistamine had approximately 16% the potency of histamine as an agonist on the in vitro guinea-pig ileum (a mepyraminesensitive response) but only 2 4 % of the activity on the in vitro guinea-pig atrium or in vivo as a stimulant of gastric acid secretion in the anaesthetized rat (14, 15). Conversely, 4-methylhistamine had approximately 40% of the potency of histamine on gastric secretion but only 0.2% the potency on the isolated ileum. In 1966 Ash & Schild (16) published a paper in which they used a series of histamine analogues to further this analysis using a range of tissues and characterized the histamine receptor that was blocked by mepyramine as the histamine HIreceptor and the other as the non-HI-receptor. Structural modification of the ethylamine side chain of histamine led to the discovery of the first 'lead' compound N"-guanylhistamine (17). This compound proved to be a weak partial agonist. Lengthening the side chain led to SK&F 91486 (18), which had increased potency but which still retained some agonist activity. A thiourea analogue, SK&F 91581 (19), was less active as an antagonist but did not have any agonist activity, and this compound was the direct precursor of the first compound to have sufficient selectivity and potency to define the second class of histamine receptor-the histamine Hzreceptor. This compound was burimamide, and its properties were described by Black et al. (20) in a publication in Nature in 1972. Burimamide was shown to be a competitive and relatively selective antagonist at the histamine H, receptor, using the ileal, uterine, and atrial assays described above. Burimamide was also found to inhibit histamine-stimulated gastric acid secretion in various species, which established the existence of H, receptors on the acid-secreting parietal cell. Perhaps more importantly, burimamide was also found to inhibit acid secretion evoked by other stimulae, such as pentagastrin, and this led to the establishment of a key role for histamine in the
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M . E. Parsons
physiologic control of gastric acid secretion (21) (see also article by Obrink in this supplement). The ability of burimamide to inhibit stimulated acid secretion was also demonstrated in man, but its low oral potency precluded its development for therapeutic use. Substitution of a methyl group into the imidazole ring (at the 4-position) and a sulphur atom in the side chain led to the synthesis of metiamide, a compound some ten times more potent than burimamide which was also orally active (22). Metiamide was examined clinically and found to be effective in the therapy of peptic ulcer diseases, confirming a central role for acid secretion in the aetiology of these diseases. Unfortunately, the compound had to be withdrawn when several cases of reversible granulocytopaenia were uncovered during human clinical trials. Concern was expressed that this was a consequence of the pharmacology of the compound-that is, its ability to block histamine H 2 receptors. However, it was felt likely that this toxic effect was associated with the presence of a thiourea group in the molecule, and this led to the investigation of non-thiourea analogues. This approach was successful and furnished the cyanoguanidine analogue cimetidine (TagametB (23). This compound lacked the toxicity of metiamide and has proved highly effective in the therapy of acid-related diseases. becoming the world’s first billion-dollar selling drug. HISTAMINE H2-RECEPTOR ANTAGONISTS AFTER CIMETIDINE Research at Glaxo laboratories led to the development of the second marketed histamine H 2 receptor antagonist ranitidine (ZantacB) (24). Depending on the experimental circumstances and, in particular, on the gastric secretory stimulant used, ranitidine has a potency some two to ten times that of cimetidine and. like cimetidine. has proved therapeutically efficacious in a range of acid-related diseases. Subsequently, other H2 antagonists have been developed, such as famntidine (Pepcidn). nizatidine (Axid@’),and roxatidine. Although they belong to a range of chemical classes and differ widely in their
potency, the duration of action of all of these recently developed compounds is similar to that of cimetidine. In the early days of the development of both cimetidine and ranitidine it was considered that, to obtain effective healing of peptic ulcers, it was necessary to control acid secretion for the whole of each 24-h period. For this reason, dosing four times a day was standard clinical practice, since the duration of action of these compounds was relatively short. This led to the search for longeracting H2antagonists. Both Smith Kline & French and Glaxo synthesized such compounds. SK&F 93479 (lupitidine) not only had a duration of action longer than that of cimetidine but was also some sixteen times more potent (25). Glaxo synthesized lamtidine and loxtidine (26), which proved to be extremely long-acting H2 antagonists with antisecretory activity exerted throughout a 24-h period. Although both SK&F 93479 and loxtidine were taken into development, neither compound reached the market place. This was because in the 2-year rat carcinogenicity studies both compounds caused the formation of gastric carcinoid tumours (27, 28). This effect was believed to be due, in part a t least, to the profound and sustained inhibition of acid secretion, which led in turn to sustained hypergastrinaemia. Gastrin via its trophic action was thought to cause mucosal hyperplasia and eventually carcinoid formation. A n analogous situation has been seen with another long-acting antisecretory compound, the H+/K+ ATPase inhibitor omeprazole and is discussed in detail in another article in this supplement. It is slightly ironical that while drug companies searched for long-acting H 2 antagonists, the prescribing habits with the short-acting compounds was changing first t o twice a day dosing and more recently to a single dose at nighttime, the latter presumably reflecting the importance of nocturnal acid secretion in the aetiology and symptoms of peptic ulcer disease. SELECTIVE HI A N D HZ AGONISTS The existence of selective ligands for antagonizing the actions of histamine at H , and H 2 receptors
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Histamine Receptors
has helped to increase our understanding of the role of histamine in various physiologic and pathologic circumstances. Selective agonists for the two receptors would also be useful analytical tools. As noted above, 2- and 4-methylhistamine showed some degree of selectivity for the H, and H2 receptor, respectively. However, for the former compound the H1/H2 ratio was only approximately 4, whereas for 4-methylhistamine the H2/ H I ratio was approximately 200. Subsequently, H2 agonists of even greater selectivity have been developed, such as dimaprit (29), which has no agonist activity at the H I receptor at concentrations up to 100 FM but had 71% the activity of histamine on the H 2 receptor on the guineapig atrium. The ultimate in selectivity is afforded by impromidine (30) (but see below), which is devoid of H I agonist activity at 1 mM but is more potent than histamine itself at the H 2 receptor having, for example, 17 times the potency of histamine in stimulating gastric acid secretion in the anaesthetized rat. Under certain circumstances, however, impromidine can act as a partial agonist at the H2 receptor, which may complicate the interpretation of results obtained using this compound. Progress in the field of developing selective H, agonists has been far less satisfactory and, although some improvement has been made over 2-methylhistamine, this has not been as spectacular as in the H2 agonist area. 2-Pyridylethylamine shows some degree of selectivity for the H , receptor, but its activity at the Hz receptor varies from tissue to tissue (14). The most selective H i agonist synthesized to date is 2-thiazolylethylamine (14), but even in this case the H I / H 2 potency ratio is only in the order of ten, so that care must be taken in interpreting data obtained using this compound. THE HISTAMINE H3 RECEPTOR Strong evidence for further heterogenicity among histamine receptor populations was first provided in 1983 by Schwartz and co-workers (31). although there had been earlier suggestions that an ‘atypical’ histamine receptor existed (32. 33). The Pans group showed that exogenously applied
49
histamine could inhibit K+ depolarized histamine release from rat brain cortical slices via what they suggested was a presynaptic histamine autoreceptor. Using a range of agonists and antagonist., the authors concluded that the receptor involved was neither H I nor H 2 and was designated H3. They found, for example, that the selective H2 agonist dimaprit and impromidine were inactive, whereas the side chain methyl analogues Na-methylhistamine and N,N-dimethylhistamine were more potent as agonists than histamine itself. Subsequently, they demonstrated that impromidine, which had hitherto been regarded as a selective H2 agonist, was also a fairly potent H3 antagonist with a pA2 value in their assay system of 7.52 (31). Similarly, burimamide, which was thought to be a relatively weak but selective H2 antagonist, was found to be significantly more potent as an antagonist at the H 3 receptor. These latter observations help to explain some of the earlier anomalous results obtained with these compounds but also mean that care must be taken in carrying out experimental studies with burimamide and impromidine. The second major breakthrough in the histamine H 3 receptor field came with the discovery of highly selective ligands for this receptor (34). The stereoselective compound Ra-methylhistamine has a high potency as an agonist at the H, receptor (15 times more potent than histamine) but with only very weak agonist activity at the H i and Hz receptors. In contrast, thioperamide is a potent and selective H3 antagonist with a pA2 value against histamine in the brain of 8.96. DISTRIBUTION OF HISTAMINE RECEPTORS With the advent of selective agonists and antagonists for the three subclasses of histamine receptors, tools became available for the analysis of the distribution of histamine receptors. Perhaps not surprisingly, given the ubiquitous nature of the substance, histamine receptors have been identified on virtually every tissue in the body, although it is clear that not all three classes of receptor are represented on every tissue. Clearly,
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M . E. Parsons
Table I. Tissues/organs containing histamine receptors Histamine receptor ~~~
Brain
Cardiovascular system Gut Urinogenital
Respiratory immune
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it would be inappropriate in an article of this kind to provide a comprehensive survey of the evidence supporting the existence of histamine receptors in a particular tissue, and readers are referred to a book on the Pharmacology of Histamirie Receptors (35). which although slightly out of date (€I3 receptors are not covered) is reasonably broad in its treatment of the subject. Table 1 indicates the major organs and tissues in which histamine receptors have been identified. In the stomach the existence of H2 receptors on the parietal cell and their key role in the physiologic control of gastsic acid secretion has received widespread attention (see article by K. Obrink in this supplement). However, it should be noted that histamine can also affect the smooth muscle of the stomach (and other parts of the gastrointestinal tract). although the effects are complex, involving indirect cholinergic pathways as well as direct effects on both HI and H2 receptors (36.37). To date. little work has been published concerning the existence of the H3 receptors in the gastrointestinal tract, although the selective H 3 agonist Rct-methylhistamine has been reported to inhibit pentagastrin-stimulated acid secretion (38). Two studies on the guineapig ileum suggest that histamine inhibits acetylcholine-mediated effects, such as electrically evoked contractions, in the gastrointestinal tract via presynaptically located Hi receptors. Both H I and H1receptors have been identified in the cardiovascular system of all species studied. and in most species, activation of both receptor classes leads to a fail in blood pressure caused mainly by a dilatation of resistance vessels (39). In the stomach the effect of histamine in increasing mucosal blood flow is a consequence of direct
vasodilatation of the gastric resistance vessels activated by both H I and H2receptors and an indirect component that may be secondary to H2-receptormediated gastric acid secretion (40). The effects of histamine on the respiratory tract are complex including, as they do, not only actions on respiratory smooth muscle but also on the respiratory vasculature and o n fluid secretion and immunopharmacologic effects on mast cell and lymphocytes. Many of these effects involve H , and H2 receptors, and recently. evidence for the existence of H3 receptors modulating neurally induced bronchoconstriction has been provided (41). Histamine may have an important role in both the expression and control of immune responses, and histamine receptors are present on mast cells and basophils. In the main, these receptors are of the Hz class, although significant densities of Hireceptoi sites have been identified on guinea-pig lung, where they are assumed to be associated with mast cells (34). All three classes of histamine receptor are widely distributed in the brain associated either with histaminergic neurons or mast cells. The sedative effects of many classical antihistaminic drugs are assumed to be due to blockade of H , receptors in the cerebral cortex. It was, of course. on brain tissue that the histamine H 3receptor was first identified, and recently a role for histamine acting at H3 receptors in the control of motor activity has been suggested (42). POTENTIAL T H E R A P E U T I C USES OF HISTAMINE AGONISTS A N D ANTAGONISTS It is perhaps surprising given the widespread distribution of histamine receptors that histamine ligands have found only limited therapeutic application. Histamine H ,-receptor antagonists are extensively used in the symptomatic treatment of allergic disorders such urticaria. allergic dermatoses, pruritus, and seasonal rhinitis, and H2-receptorantagonists have proved highly effective in the therapy of acid-related diseases such as peptic ulcer. Extensive use of H2 antagonists in man has
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Histamine Receptors
shown them to be without limiting side effects, but with many H1 antagonists the clinical effectiveness can be limited by dose restriction due to their central depressant properties. However, compounds with markedly reduced centrally mediated side effects have now been marketed such as terfenadine and astemizole (43). This lack of side effects suggests that under normal circumstances histamine acting at either H I or Hz receptors has a limited physiologic role. The same may well not be true under pathologic conditions. Histamine antagonists have been studied clinically in various disorders. such as cluster headache and migraine, without clear demonstration of clinical benefit. The reason is likely to be that mediators in addition to, or other than, histamine are released and act to produce the symptoms. Despite the presence of histamine receptors on the heart and peripheral vasculature, no physiologic role for histamine has been defined in the cardiovascular system, and it seems that histamine antagonists will have a therapeutic role in, for example, cardiac disease only if histamine is involved in the pathogenesis of arrhythmias. Lorenz et al. (44) have advocated the use of a combination of H I and H2 antagonists to prevent anaphylactoid reactions to plasma expanders such as Haemaccel@. With regard to the respiratory system, H , antagonists have proved disappointing in the treatment of asthma, but this may in part by a consequence of side effects limiting the dosage used. The demonstration of H3 receptors in the respiratory tract (see above) has led to trials being conducted with the selective H 3 agonist Ramethylhistamine in pneumoallergic disorders. Despite the presence of all three types of histamine receptors, our understanding of possible physiologic or pathologic roles for histamine in the immune and central nervous systems is very limited. More intensive preclinical investigation will be necessary before any therapeutic target may be identified. REFERENCES I . Dale HH, Laidlaw PP. The physiological action of iminazolylethylamine. J Physiol 1910. 41[B], 318344
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2. Dale HH, Laidlaw PP. Further observations on the action of beta-imidazolyl-ethylamine.J Physiol 1911,43, 182-195 3. Dale HH, Laidlaw PP. Histamine shock. J Physiol 1919, 52, 355-390 4. Popielski L. /Mmidazolylathylamine und de organextrakte: /3-Imidazolylathylamine als machtiger erreger der magendruson. Pfluegers Arch 1920, 178, 214-226 5. Bovet D, Staub A-M. Action protectrice des ethers phenoliques au cows de I'intoxication histaminique. C R SOC Biol (Pans) 1937, 125, 547-549 6. Bovet D, Horclois R, Walthert F. ProprietCs antihistaminique de la N-p-methoxybenzyl N-dimethylaminoethyl-a-amino-pyridine.CR Soc Biol (Paris) 1944, 138, 99-100 7. Loew ER, MacMillan R, Kaiser ME. Antihistamine properties of benadryl, P-dimethylaminoethyl benzhydryl ether hydrochloride. J Pharmacol Exp Ther 1946, 86, 229-238 8. Halpern BN, Mauric G , Etude quantitative de I'antagonisme de l'histamine et d'un antihistaminique de synthese (Antergan) sur I'intestin isolC de cobaye. C R Soc Biol (Paris) 1946, 140,440-443 9. Schild HO. PA, A new role for the measurement of drug antagonism. Br J Pharmacol Chemother 1947, 2, 189-206 LO. Trendelenburg U . The action of histamine and 5hydroxytryptamine on isolated mammalian atria. J Pharmacol Exp Ther 1960, 130, 450-460 11. Dews PB, Graham JDP. The antihistamine substance 2786 RP. Br J Pharmacol Chemother 1946, 1, 278-286 12. Loew ER. Pharmacology of antihistamine compounds. Physiol Rev 1947, 27, 542-573 13. Folkow B, Haeger K, Kahlson G . Observations on reactive hyperaemia as related to histamine, on drugs antagonising vasodilatation induced by histamine and on vasodilator properties of adenosine triphosphate. Acta Physiol Scand 1948, 15, 264-278 4. Ganellin CR. Chemistry and structure-activity relationships of drugs acting at histamine receptors. In: Ganellin CR, Parsons ME, eds. Pharmacology of histamine receptors. Wright PSG, Bistol, 1982, 10-102 5. Parsons ME. Quantitative studies of drug-induced acid gastric secretion [Ph.D. Thesis]. University of London, London, 1969 16. Ash ASF, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol Chemother 1966. 27, 427-439 17. Durant GJ, Parsons ME, Black JW. Potential histamine Hz-receptor antagonists. 2,N"-guanylhistamine. J Med Chem 1975, 18, 830-833 18. Parsons ME, Blakemore RC, Durant GJ, Ganellin CR, Rasmussen AC. 3-[4-(5)-Imidazolyl]-propylguanidine (SK&F 91486)-a partial agonist at histamine H2-receptors. Agents Actions 1975, 5. 464 19. Ganellin CR. Selectivity and design of histamine H2-receptor antagonists. J Appl Chem Biotechnol 1978, 28, 183-200 20. Black JW, Duncan WAM, Durant GJ. Ganellin CR, Parsons ME. Definition and antagonism of histamine H,-receptors. Nature 1972.236,385-390
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histamine in cat bronchus. Agents Actions 1977, 7, 21, Parsons ME. Mechanism of acid secretion. In: Jew183-190 ell DR. Lowes JR. eds. Topics in gastroenterology. Vol. 16. Blackwell Scientific Publications, Oxford 33. Ambache N,Kilick SW, Aboo Zar M. Antagonism by burimamide of inhibition induced by histamine in 1989. 39-48 plexus containing longitudinal muscle preparations 22. Black JW, Duncan WAM, Emmett JC, et al. Metifrom the guinea-pig ileum. Br J Pharmacol 1973, amide-an orally active histamine H,-receptor 48, 362P-363P antagonist. Agents Actions 1973, 3. 133-137 23. Brimblecombe RW. Duncan WAM, Durant GJ, et 34. Arrang J-M, Garbarg M, Lancelot JC, eta]. Highly potent and selective ligands for histamine H1-recepal. Characterization and development of cimetidine tors. Nature 1987. 327, 117-123 as a histamine H,-receptor antagonist. Gastro35. Ganellin CR, Parsons ME, eds. Pharmacology of enterology 1978. 74, 339-347 histamine receptors. Wright PSG, Bristol, 1982 24. Bradshaw J , Brittain RT, Clitherow JW, et al. Ranitidine (AH 19065): a new potent, selective his- 36. Paton WDM, Vane JR. An analysis of the response of the isolated stomach to electrical stimulation and tamine H,-receptor antagonist. Br J Pharmacol drugs. J Physiol 1963, 165. 1&46 1979. 64. 464P 25. Blakemore RC. BrownTH. Durant GJ, et al. SK&F 37. Ohga A, Taneika T. HI- and HI-receptors in t h e smooth muscle of the ruminant stomach. Br J Phar93479, a potent and long acting histamine H,-recepmacol 1978, 62, 333-337 tor antagonist. Br J Pharmacol 1981, 74, 200P 26. Stables R. Daly MJ, Humphray J . Comparison of 38. HervatinF, Dubrasquet M, Lewin MJM. Histamine H,-receptors in the regulation of gastrin stimulated the antisecretory potency and duration of action of gastric acid secretion in the conscious cat. Gasthe Hz-receptor antagonist AH 22216, cimetidine. troenterology 1989. 96. A207 rantidine and SK&F 93479 in the dog. Agents 39. Flynn SB. Owen DAA. Histamine receptors in perActions 1983. 13. 166168 ipheral vascular beds in the cat. Br J Pharmacol 77. Betton GR, Salmon GK. Neuroendocrine carcinoid 1975. 55, 181-188 tumours of the glandular stomach of the rat following treatment with the H1-receptor antagonist 40. Harvey CA, Owen DAA. Shaw KD. Evidence for both histamine H I - and Hz-receptors in cat gastric SK&F 93479. 26th Congress of the European vasculature. Br J Pharmacol 1980, 69, 21-28 Society of Toxicology. 1985, Kupio, Abstract P32 28. Poynter D, Pick CR, Harcourt RA, et al. Associ- 41. Ichinose M,Stretton CD, Schwartz J-C, Barnes PJ. Histamine H,-receptors inhibit cholinergic neuroation of long lasting unsurmountablc histamine H1 transmission in guinea-pig airways. Br J Pharmacol blockade and gastric carcinoid tumours in the rat. 1989. 97. 13-15 Gut 1YX5. 26, 1284-1295 7 0 . Parsons ME, Owen DAA. Ganellin CR, Durant 42. Bristow LJ. Bennett GW. A role for histamine H3GJ. Dimaprit-(5-[3-(N,N-dimethylamino)-propyl]- receptors in histamine induced hypoactivity in the rat. Br J Pharmacol 1988, 94, 319P isothiourea)-a highly specific histamine H,-receptor agonist. I. Pharmacol Agents Actions 1977. 7. 43. Durant GJ, Ganellin CR, Griffiths R, Harvey CA, Owen DAA, Sach GS. Some newer HI-receptor 3 1-37 histamine antagonists. In: Ganellin CR. Schwartz 30. Durant GJ.Duncan WAM. Ganellin CR. Parsons J-C, eds. Advances in the biosciences. Vol. 51. ME. Blakemore RC. Rasmussen AC. Impromidine Frontiers in histamine research. Pergammon Press. (SKKrF 92676) is a very potent and selective agonist Oxford, 1985, 3-11 for histamine H,-receptors. Nature 1978, 276. 40344. Lorenz W, Doenicke A, Schoning B, et al. H I and 40.5 Hz-receptorantagonists for premedication in anaes31. Arrang J-M. Garbarg M. Schwartz J-C. Auto-inhithesia and surgery: a critical view based on ranhition o f brain histamine release mediated by a domized clinical trials with haemaccel and various novel class (HI)of histamine receptor. Nature 1983, antiallergic drugs. Agents Actions 1980, 10, 114302. 832-837 124 32 Chang N . Eyre P. Atypical (relaxant) response to .-
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Session 2: Histamine Receptors: An Overview M. E. Parsons To cite this article: M. E. Parsons (1991) Session 2: Histamine Receptors: An Overview, Scandinavian Journal of Gastroenterology, 26:sup180, 46-52, DOI: 10.3109/00365529109093177 To link to this article: http://dx.doi.org/10.3109/00365529109093177
Published online: 08 Jul 2009.
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Histamine Receptors: An Overview M . E . PARSONS Smith Kline & French Research Ltd., Welwyn, Herts, U.K.
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Parsons ME. Histamine receptors: an overview. Scand J Gastroenterol1991,26(suppl 180), 46-52 Histamine is widely distributed throughout the body and has a broad range of pharmacologic effects. The advent of selective agonists and antagonists has allowed the identification and characterization of three types of histamine receptor. These same compounds have helped in our understanding of physiologic and pathologic roles for histamine. Clearly, histamine plays a central role in the physiologic control of gastric acid secretion. and this fact has led to the use of Hz antagonists such as cimetidine, and ranitidine is the therapy of acid-related diseases such as peptic ulcer. Histamine is also one of the prime mediators of a variety of allergic reactions, and H, antagonists play a therapeutic role in this context. However, despite the widespread distribution of histamine receptors in, for example, the central nervous, respiratory, cardiovascular, and immune systems, other physiologic roles for histamine have not been established. It is to be hoped that future research will alter this situation and possibly lead to other therapeutic indications for histamine agonists and antagonists.
Key words: Acid secretion; agonists; allergy; antagonists; histamine: H, receptors; H2 receptors; H3 receptors
M . E. Pursons, M.D., Smith Klirie & French Research Lld, The Frythe. Welwyn. H e m , AL6 9AR. U. K .
Receptors are the molecular sites where chemical messengers act. Their definition and classification require the availability of interacting ligandsthat is, agonists and antagonists-and. therefore, the major part of this chapter will address the development of these ligands. Histamine is widely distributed throughout the body and has a range of biologic actions. Many of these were first described in a series of papers by Dale & Laidlaw (1-3). Histamine was found to contract various smooth-muscle tissues from, for example, the respiratory and gastrointestinal tract and to cause a fall in blood pressure in experimental animals. Interestingly, the ability of histamine to stimulate gastric acid secretion was not established until 1920 by Popielski (4). ANTIHISTAMINES A possible pathologic role for histamine in various allergic and inflammatory disorders led to the
search for selective antagonists of the actions of histamine, and the first of these were the Fourneau antihistamines described by Bovet & Staub ( 5 ) . These compounds were found to antagonize the contractile effect of histamine on smooth muscle and to protect guinea-pigs against lethal doses of histamine causing bronchoconstriction. Subsequently, more potent histamine antagonists were synthesized, such as mepyrarnine (6) and diphenhydramine (7). Quantitative data obtained from studies on isolated smooth muscle by Halpern & Mauric (8) suggested that the mode of action at the receptor was competitive--that is, the antagonism they produced was surmountable-and in 1947 Schild (9) introduced PA, values to characterize antagonists. These antagonists were used to establish the criteria for comparing receptors in different tissues, and the establishment of similar pA2 values for a given antagonist in a range of tissues suggested receptor homogeneity.
Histamine Receptors
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THE IDENTIFICATION OF A SECOND CLASS OF HISTAMINE RECEPTORS With the advent of selective antihistamine drugs mapping of the distribution of histamine receptors could be performed. It became apparent at a relatively early stage, however, that even potent antagonists such as diphenhydramine failed to inhibit all the pharmacologic effects of histamine. Histamine produces a positive chronotropic effect on the isolated heart or atrium of most mammalian species, and this effect is not antagonized by classical antihistamines in concentrations that are sufficient to block selectively the histamine receptors on, for example, the guinea-pig ileum (10). Dews & Graham (11) showed that the effect of histamine in inhibiting the spontaneous or evoked contractions of the isolated rat uterus was completely refractory to antagonism by antihistaminic drugs. The inability of antihistamines to antagonize histamine-stimulated acid secretion was also established at an early stage (12). The first suggestion that histamine might produce responses by interaction with two receptor sites was made by Folkow et al. in 1948 (13). They found that in cats and dogs the fall in blood pressure induced by moderate doses of histamine could be reduced by diphenhydramine, but the responses to larger doses were refractory. It is interesting to note that this paper was published in the same year as Ahlquest first defined two adrenoceptors, the a and p adrenoceptor.
THE DEVELOPMENT OF HISTAMINE Hz-RECEPTOR ANTAGONIST In 1964 Black and his colleagues at Smith Kline and French started a research program directed towards establishing the existence of a second class of histamine receptors and to develop selected antagonists for this hypothecated receptor. Black drew an analogy with the adrenergic field (in which he had played a major role in the development of p receptor antagonists) and suggested that if a second class of histamine receptor existed, ligands to interact with it would be chemically closely related to histamine itself. Further evidence for receptor heterogeneity
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was provided by the finding that simple methyl analogues of histamine showed different potencies relative to histamine depending on the assay system used (an analysis similar to that used by Ahlquest to establish adrenoceptor heterogeneity). Thus, 2-methylhistamine had approximately 16% the potency of histamine as an agonist on the in vitro guinea-pig ileum (a mepyraminesensitive response) but only 2 4 % of the activity on the in vitro guinea-pig atrium or in vivo as a stimulant of gastric acid secretion in the anaesthetized rat (14, 15). Conversely, 4-methylhistamine had approximately 40% of the potency of histamine on gastric secretion but only 0.2% the potency on the isolated ileum. In 1966 Ash & Schild (16) published a paper in which they used a series of histamine analogues to further this analysis using a range of tissues and characterized the histamine receptor that was blocked by mepyramine as the histamine HIreceptor and the other as the non-HI-receptor. Structural modification of the ethylamine side chain of histamine led to the discovery of the first 'lead' compound N"-guanylhistamine (17). This compound proved to be a weak partial agonist. Lengthening the side chain led to SK&F 91486 (18), which had increased potency but which still retained some agonist activity. A thiourea analogue, SK&F 91581 (19), was less active as an antagonist but did not have any agonist activity, and this compound was the direct precursor of the first compound to have sufficient selectivity and potency to define the second class of histamine receptor-the histamine Hzreceptor. This compound was burimamide, and its properties were described by Black et al. (20) in a publication in Nature in 1972. Burimamide was shown to be a competitive and relatively selective antagonist at the histamine H, receptor, using the ileal, uterine, and atrial assays described above. Burimamide was also found to inhibit histamine-stimulated gastric acid secretion in various species, which established the existence of H, receptors on the acid-secreting parietal cell. Perhaps more importantly, burimamide was also found to inhibit acid secretion evoked by other stimulae, such as pentagastrin, and this led to the establishment of a key role for histamine in the
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M . E. Parsons
physiologic control of gastric acid secretion (21) (see also article by Obrink in this supplement). The ability of burimamide to inhibit stimulated acid secretion was also demonstrated in man, but its low oral potency precluded its development for therapeutic use. Substitution of a methyl group into the imidazole ring (at the 4-position) and a sulphur atom in the side chain led to the synthesis of metiamide, a compound some ten times more potent than burimamide which was also orally active (22). Metiamide was examined clinically and found to be effective in the therapy of peptic ulcer diseases, confirming a central role for acid secretion in the aetiology of these diseases. Unfortunately, the compound had to be withdrawn when several cases of reversible granulocytopaenia were uncovered during human clinical trials. Concern was expressed that this was a consequence of the pharmacology of the compound-that is, its ability to block histamine H 2 receptors. However, it was felt likely that this toxic effect was associated with the presence of a thiourea group in the molecule, and this led to the investigation of non-thiourea analogues. This approach was successful and furnished the cyanoguanidine analogue cimetidine (TagametB (23). This compound lacked the toxicity of metiamide and has proved highly effective in the therapy of acid-related diseases. becoming the world’s first billion-dollar selling drug. HISTAMINE H2-RECEPTOR ANTAGONISTS AFTER CIMETIDINE Research at Glaxo laboratories led to the development of the second marketed histamine H 2 receptor antagonist ranitidine (ZantacB) (24). Depending on the experimental circumstances and, in particular, on the gastric secretory stimulant used, ranitidine has a potency some two to ten times that of cimetidine and. like cimetidine. has proved therapeutically efficacious in a range of acid-related diseases. Subsequently, other H2 antagonists have been developed, such as famntidine (Pepcidn). nizatidine (Axid@’),and roxatidine. Although they belong to a range of chemical classes and differ widely in their
potency, the duration of action of all of these recently developed compounds is similar to that of cimetidine. In the early days of the development of both cimetidine and ranitidine it was considered that, to obtain effective healing of peptic ulcers, it was necessary to control acid secretion for the whole of each 24-h period. For this reason, dosing four times a day was standard clinical practice, since the duration of action of these compounds was relatively short. This led to the search for longeracting H2antagonists. Both Smith Kline & French and Glaxo synthesized such compounds. SK&F 93479 (lupitidine) not only had a duration of action longer than that of cimetidine but was also some sixteen times more potent (25). Glaxo synthesized lamtidine and loxtidine (26), which proved to be extremely long-acting H2 antagonists with antisecretory activity exerted throughout a 24-h period. Although both SK&F 93479 and loxtidine were taken into development, neither compound reached the market place. This was because in the 2-year rat carcinogenicity studies both compounds caused the formation of gastric carcinoid tumours (27, 28). This effect was believed to be due, in part a t least, to the profound and sustained inhibition of acid secretion, which led in turn to sustained hypergastrinaemia. Gastrin via its trophic action was thought to cause mucosal hyperplasia and eventually carcinoid formation. A n analogous situation has been seen with another long-acting antisecretory compound, the H+/K+ ATPase inhibitor omeprazole and is discussed in detail in another article in this supplement. It is slightly ironical that while drug companies searched for long-acting H 2 antagonists, the prescribing habits with the short-acting compounds was changing first t o twice a day dosing and more recently to a single dose at nighttime, the latter presumably reflecting the importance of nocturnal acid secretion in the aetiology and symptoms of peptic ulcer disease. SELECTIVE HI A N D HZ AGONISTS The existence of selective ligands for antagonizing the actions of histamine at H , and H 2 receptors
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Histamine Receptors
has helped to increase our understanding of the role of histamine in various physiologic and pathologic circumstances. Selective agonists for the two receptors would also be useful analytical tools. As noted above, 2- and 4-methylhistamine showed some degree of selectivity for the H, and H2 receptor, respectively. However, for the former compound the H1/H2 ratio was only approximately 4, whereas for 4-methylhistamine the H2/ H I ratio was approximately 200. Subsequently, H2 agonists of even greater selectivity have been developed, such as dimaprit (29), which has no agonist activity at the H I receptor at concentrations up to 100 FM but had 71% the activity of histamine on the H 2 receptor on the guineapig atrium. The ultimate in selectivity is afforded by impromidine (30) (but see below), which is devoid of H I agonist activity at 1 mM but is more potent than histamine itself at the H 2 receptor having, for example, 17 times the potency of histamine in stimulating gastric acid secretion in the anaesthetized rat. Under certain circumstances, however, impromidine can act as a partial agonist at the H2 receptor, which may complicate the interpretation of results obtained using this compound. Progress in the field of developing selective H, agonists has been far less satisfactory and, although some improvement has been made over 2-methylhistamine, this has not been as spectacular as in the H2 agonist area. 2-Pyridylethylamine shows some degree of selectivity for the H , receptor, but its activity at the Hz receptor varies from tissue to tissue (14). The most selective H i agonist synthesized to date is 2-thiazolylethylamine (14), but even in this case the H I / H 2 potency ratio is only in the order of ten, so that care must be taken in interpreting data obtained using this compound. THE HISTAMINE H3 RECEPTOR Strong evidence for further heterogenicity among histamine receptor populations was first provided in 1983 by Schwartz and co-workers (31). although there had been earlier suggestions that an ‘atypical’ histamine receptor existed (32. 33). The Pans group showed that exogenously applied
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histamine could inhibit K+ depolarized histamine release from rat brain cortical slices via what they suggested was a presynaptic histamine autoreceptor. Using a range of agonists and antagonist., the authors concluded that the receptor involved was neither H I nor H 2 and was designated H3. They found, for example, that the selective H2 agonist dimaprit and impromidine were inactive, whereas the side chain methyl analogues Na-methylhistamine and N,N-dimethylhistamine were more potent as agonists than histamine itself. Subsequently, they demonstrated that impromidine, which had hitherto been regarded as a selective H2 agonist, was also a fairly potent H3 antagonist with a pA2 value in their assay system of 7.52 (31). Similarly, burimamide, which was thought to be a relatively weak but selective H2 antagonist, was found to be significantly more potent as an antagonist at the H 3 receptor. These latter observations help to explain some of the earlier anomalous results obtained with these compounds but also mean that care must be taken in carrying out experimental studies with burimamide and impromidine. The second major breakthrough in the histamine H 3 receptor field came with the discovery of highly selective ligands for this receptor (34). The stereoselective compound Ra-methylhistamine has a high potency as an agonist at the H, receptor (15 times more potent than histamine) but with only very weak agonist activity at the H i and Hz receptors. In contrast, thioperamide is a potent and selective H3 antagonist with a pA2 value against histamine in the brain of 8.96. DISTRIBUTION OF HISTAMINE RECEPTORS With the advent of selective agonists and antagonists for the three subclasses of histamine receptors, tools became available for the analysis of the distribution of histamine receptors. Perhaps not surprisingly, given the ubiquitous nature of the substance, histamine receptors have been identified on virtually every tissue in the body, although it is clear that not all three classes of receptor are represented on every tissue. Clearly,
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M . E. Parsons
Table I. Tissues/organs containing histamine receptors Histamine receptor ~~~
Brain
Cardiovascular system Gut Urinogenital
Respiratory immune
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Skin
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it would be inappropriate in an article of this kind to provide a comprehensive survey of the evidence supporting the existence of histamine receptors in a particular tissue, and readers are referred to a book on the Pharmacology of Histamirie Receptors (35). which although slightly out of date (€I3 receptors are not covered) is reasonably broad in its treatment of the subject. Table 1 indicates the major organs and tissues in which histamine receptors have been identified. In the stomach the existence of H2 receptors on the parietal cell and their key role in the physiologic control of gastsic acid secretion has received widespread attention (see article by K. Obrink in this supplement). However, it should be noted that histamine can also affect the smooth muscle of the stomach (and other parts of the gastrointestinal tract). although the effects are complex, involving indirect cholinergic pathways as well as direct effects on both HI and H2 receptors (36.37). To date. little work has been published concerning the existence of the H3 receptors in the gastrointestinal tract, although the selective H 3 agonist Rct-methylhistamine has been reported to inhibit pentagastrin-stimulated acid secretion (38). Two studies on the guineapig ileum suggest that histamine inhibits acetylcholine-mediated effects, such as electrically evoked contractions, in the gastrointestinal tract via presynaptically located Hi receptors. Both H I and H1receptors have been identified in the cardiovascular system of all species studied. and in most species, activation of both receptor classes leads to a fail in blood pressure caused mainly by a dilatation of resistance vessels (39). In the stomach the effect of histamine in increasing mucosal blood flow is a consequence of direct
vasodilatation of the gastric resistance vessels activated by both H I and H2receptors and an indirect component that may be secondary to H2-receptormediated gastric acid secretion (40). The effects of histamine on the respiratory tract are complex including, as they do, not only actions on respiratory smooth muscle but also on the respiratory vasculature and o n fluid secretion and immunopharmacologic effects on mast cell and lymphocytes. Many of these effects involve H , and H2 receptors, and recently. evidence for the existence of H3 receptors modulating neurally induced bronchoconstriction has been provided (41). Histamine may have an important role in both the expression and control of immune responses, and histamine receptors are present on mast cells and basophils. In the main, these receptors are of the Hz class, although significant densities of Hireceptoi sites have been identified on guinea-pig lung, where they are assumed to be associated with mast cells (34). All three classes of histamine receptor are widely distributed in the brain associated either with histaminergic neurons or mast cells. The sedative effects of many classical antihistaminic drugs are assumed to be due to blockade of H , receptors in the cerebral cortex. It was, of course. on brain tissue that the histamine H 3receptor was first identified, and recently a role for histamine acting at H3 receptors in the control of motor activity has been suggested (42). POTENTIAL T H E R A P E U T I C USES OF HISTAMINE AGONISTS A N D ANTAGONISTS It is perhaps surprising given the widespread distribution of histamine receptors that histamine ligands have found only limited therapeutic application. Histamine H ,-receptor antagonists are extensively used in the symptomatic treatment of allergic disorders such urticaria. allergic dermatoses, pruritus, and seasonal rhinitis, and H2-receptorantagonists have proved highly effective in the therapy of acid-related diseases such as peptic ulcer. Extensive use of H2 antagonists in man has
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Histamine Receptors
shown them to be without limiting side effects, but with many H1 antagonists the clinical effectiveness can be limited by dose restriction due to their central depressant properties. However, compounds with markedly reduced centrally mediated side effects have now been marketed such as terfenadine and astemizole (43). This lack of side effects suggests that under normal circumstances histamine acting at either H I or Hz receptors has a limited physiologic role. The same may well not be true under pathologic conditions. Histamine antagonists have been studied clinically in various disorders. such as cluster headache and migraine, without clear demonstration of clinical benefit. The reason is likely to be that mediators in addition to, or other than, histamine are released and act to produce the symptoms. Despite the presence of histamine receptors on the heart and peripheral vasculature, no physiologic role for histamine has been defined in the cardiovascular system, and it seems that histamine antagonists will have a therapeutic role in, for example, cardiac disease only if histamine is involved in the pathogenesis of arrhythmias. Lorenz et al. (44) have advocated the use of a combination of H I and H2 antagonists to prevent anaphylactoid reactions to plasma expanders such as Haemaccel@. With regard to the respiratory system, H , antagonists have proved disappointing in the treatment of asthma, but this may in part by a consequence of side effects limiting the dosage used. The demonstration of H3 receptors in the respiratory tract (see above) has led to trials being conducted with the selective H 3 agonist Ramethylhistamine in pneumoallergic disorders. Despite the presence of all three types of histamine receptors, our understanding of possible physiologic or pathologic roles for histamine in the immune and central nervous systems is very limited. More intensive preclinical investigation will be necessary before any therapeutic target may be identified. REFERENCES I . Dale HH, Laidlaw PP. The physiological action of iminazolylethylamine. J Physiol 1910. 41[B], 318344
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2. Dale HH, Laidlaw PP. Further observations on the action of beta-imidazolyl-ethylamine.J Physiol 1911,43, 182-195 3. Dale HH, Laidlaw PP. Histamine shock. J Physiol 1919, 52, 355-390 4. Popielski L. /Mmidazolylathylamine und de organextrakte: /3-Imidazolylathylamine als machtiger erreger der magendruson. Pfluegers Arch 1920, 178, 214-226 5. Bovet D, Staub A-M. Action protectrice des ethers phenoliques au cows de I'intoxication histaminique. C R SOC Biol (Pans) 1937, 125, 547-549 6. Bovet D, Horclois R, Walthert F. ProprietCs antihistaminique de la N-p-methoxybenzyl N-dimethylaminoethyl-a-amino-pyridine.CR Soc Biol (Paris) 1944, 138, 99-100 7. Loew ER, MacMillan R, Kaiser ME. Antihistamine properties of benadryl, P-dimethylaminoethyl benzhydryl ether hydrochloride. J Pharmacol Exp Ther 1946, 86, 229-238 8. Halpern BN, Mauric G , Etude quantitative de I'antagonisme de l'histamine et d'un antihistaminique de synthese (Antergan) sur I'intestin isolC de cobaye. C R Soc Biol (Paris) 1946, 140,440-443 9. Schild HO. PA, A new role for the measurement of drug antagonism. Br J Pharmacol Chemother 1947, 2, 189-206 LO. Trendelenburg U . The action of histamine and 5hydroxytryptamine on isolated mammalian atria. J Pharmacol Exp Ther 1960, 130, 450-460 11. Dews PB, Graham JDP. The antihistamine substance 2786 RP. Br J Pharmacol Chemother 1946, 1, 278-286 12. Loew ER. Pharmacology of antihistamine compounds. Physiol Rev 1947, 27, 542-573 13. Folkow B, Haeger K, Kahlson G . Observations on reactive hyperaemia as related to histamine, on drugs antagonising vasodilatation induced by histamine and on vasodilator properties of adenosine triphosphate. Acta Physiol Scand 1948, 15, 264-278 4. Ganellin CR. Chemistry and structure-activity relationships of drugs acting at histamine receptors. In: Ganellin CR, Parsons ME, eds. Pharmacology of histamine receptors. Wright PSG, Bistol, 1982, 10-102 5. Parsons ME. Quantitative studies of drug-induced acid gastric secretion [Ph.D. Thesis]. University of London, London, 1969 16. Ash ASF, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol Chemother 1966. 27, 427-439 17. Durant GJ, Parsons ME, Black JW. Potential histamine Hz-receptor antagonists. 2,N"-guanylhistamine. J Med Chem 1975, 18, 830-833 18. Parsons ME, Blakemore RC, Durant GJ, Ganellin CR, Rasmussen AC. 3-[4-(5)-Imidazolyl]-propylguanidine (SK&F 91486)-a partial agonist at histamine H2-receptors. Agents Actions 1975, 5. 464 19. Ganellin CR. Selectivity and design of histamine H2-receptor antagonists. J Appl Chem Biotechnol 1978, 28, 183-200 20. Black JW, Duncan WAM, Durant GJ. Ganellin CR, Parsons ME. Definition and antagonism of histamine H,-receptors. Nature 1972.236,385-390
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