Histamine Analogues Research Articles

Specific, irreversible antagonism of histamine receptors in the isolated guinea-pig vas deferens by 4(5)-[5-(4-azido-2-nitroanilino)ethyl] imidazole, a photoaffinity analog of histamine

Photolysis of 4(5)-[2-(4-azido-2-nitroanilino)ethyl] imidazole (AAH) in organ chambers containing isolated guinea-pig vas deferens resulted in an irreversible antagonism of histamine-induced contractions of the smooth muscle. A similar antognism was found in the presence of non-photolyzed AAH, and was reversible if not irradiated. After photolysis, AAH had no effect on tissue responses to KCl, norepinephrine and MgATP; responses to acetylcholine were only slightly reduced. The tissues were protected from the antagonistic effect of photolyzed AAH if diphenhydramine, an H 1-histamine receptor antagonist, was also present during photolysis. Conversely, histamine provided no such protection while cimetidine, an H 2-histamine receptor antagonist, was weakly protective. The results indicate that AAH is a specific and irreversible histamine photoaffinity antagonist. It satisfies the chemical and pharmacological criteria for such an antagonism. The antagonism appears to result from a covalent attachment of the compound to an H 1-histamine receptor-antagonist binding site.

Pharmacological investigations into the effects of histamine and histamine analogs on guinea pig and rat uterus.

The effects of histamine and its analogs 2-(2-pyridyl) ethylamine (PEA) and 4-methylhistamine (4 MH) have been studied on uterine preparations obtained from estrogen-primed guinea pigs and rats. (1) Histamine and 4 MH, a specific H2-receptor agonist produced relaxation in estrogen-primed rat uterus, whereas these agonists produced contraction in the estrogen-primed guinea pig uterus. (2) PEA, a specific H1-receptor agonist produced contraction in the guinea pig uterus but had no effect on the rat uterus. (3) Metiamide blocked responses to histamine and 4 MH in the rat uterus, whereas mepyramine blocked responses to histamine and PEA in the guinea pig uterus. (4) Propranolol produced competitive antagonism with histamine in the rat uterus, whereas it had no significant effect on the histamine or PEA responses in the guinea pig uterus. (5) Reserpine pretreatment completely abolished the responses to histamine and 4 MH in the rat uterus but did not alter the response in the guinea pig uterus. (6) Our data suggest that in rat uterus only H2-receptors are present and they are indirectly through the release of noradrenaline. In the guinea pig uterus both H1- and H2-receptors are present and are excitatory and directly acting.

Histamine stimulation of rat gastric parietal cell adenylyl cyclase: Modulation by guanine nucleotides

Histamine activation of adenylyl cyclase activity in sonicated enriched rat gastric parietal cells showed a time, temperature, and concentration dependence upon guanine diphosphoimide (Gpp(NH)p). Enzyme activation was first order with Gpp(NH)p alone or Gpp(NH)p plus histamine. The K a for Gpp(NH)p was ~2 μ m and was not influenced by histamine. GTP and GDP were inactive alone or with histamine and were competitive with Gpp(NH)p, showing apparent K i 's of near 0.4 and 0.3 μ m, respectively. In the presence of Gpp(NH)p, parietal cell adenylyl cyclase was activated by histamine with an EC 50 of 24 μ m, the most potent in a series of histamine analogs, further substantiating an H 2-receptor classification for this response. H 2-Receptor antagonists were competitive inhibitors with submicromolar K i 's. Preincubation of parietal cells with histamine and Gpp(NH)p resulted in adenylyl cyclase activity up to 15 times the basal level. The activated state was retained after washing the cells free of histamine and Gpp(NH)p and was not reversed by the subsequent addition of either histamine, cimetidine, or GTP. The other gastric acid secretagogues, pentagastrin and carbamylcholine, were without effect upon histamine activation or the activated state of adenylyl cyclase. These results describe a level of control of histamine-sensitive adenylyl cyclase that requires consideration in the activation of the parietal cell H 2-receptor system by histamine to modulate acid secretion.

Effects of alkyl analogues of histamine and metiamide on the isolated guinea pig heart.

The effects of some substitutions in position 5(4) of the imidazole ring in the histamine and metiamide molecule were studied by means of isolated heart preparations from the guinea pig (atria and papillary muscle). Among the histamine analogues 5-methyl and 5-ethyl histamine were found to possess approximately the same intrinsic activity as histamine whereas 5-isopropylhistamine was shown to be absolutely inactive. Among the metiamide analogues the 5-ethyl derivative (etiamide) was found less effective than the parent substance but showed the same kind of competitive antagonism; the isopropyl derivative (isopropiamide) was found to be inactive up to a concentration of 3 X 10(-5) mol/l and to exert a non-competitive antagonism with 3 X 10(-4) mol/l. On the whole the atria and the papillary muscle preparations behaved quite similarly in regard to both the agonistic and the antagonistic compounds.

Histamine responsiveness of isolated gastric glands.

Gastric glands isolated from rabbit were employed to perform a pharmacological characterization of the histamine receptor associated with physiological and biochemical responses in gastric cells. Five separate response parameters were characterized using histamine analogues and histamine antagonists. The following parameters were studied: respiration, accumulation of the weak base aminopyrine, adenylate cyclase activity, cAMP accumulation, and the uptake of histamine. All parameters were examined for agonist and antagonist potency using dose-response curves, ED50 and pA2 values. Comparison of the ED50-agonist and pA2-cimetidine values showed a remarkable similarity for respiration, aminopyrine accumulation, adenylate cyclase activity, and cAMP accumulation. The agonist potency sequence and pA2 values for H2- vs. H1-receptor antagonists characterized the histamine receptor associated with these four parameters as being of the H2 type. Moreover, the similarity of pharmacological characteristics provides evidence for a similar, if not common, receptor for these responses. The histamine uptake system shows a generally lower affinity for most agonists. Although the general agonist potency sequence is similar to the other parameters, notable exceptions were found for antagonists and the typical H2-agonist, dimaprit. Thus, the uptake system does not appear to be related directly to the activation of secretion and the carrier binding site cannot be simply defined by H1 or H2 properties.

Reminiscences of the development of cimetidine

The marketing of cimetidine in the United Kingdom in November, 1976, and in the United States in August, 1977, was the culmination of a research and development program that started in the British laboratories of Smith Kline & French in 1964. The first scientific publication on H, receptor antagonists was in Nature in April 1972, and in the following 4-5 yr this literature had grown to some 700 papers, of which approximately 125 related to studies in humans. The development of the H, receptc.r antagonists and the chemical thinking that led to the original discovery of burimamide, and subsequently to metiamide and cimetidine, has been well documented,le3 but the problems, both human and scientific, that were encountered and resolved between the inception of the program in 1964 and its successful conclusion in November, 1976, have not been published. The first formal proposal that SK&F should invest in the discovery of a new type of histamine antagonist was made by Dr. Edward Paget (then Research Director of the British laboratories) in June, 1964, following discussions with Dr. James Black. Paget recorded “None of the known antihistamines are effective antagonists of histamine-stimulated gastric secretion . . . it is obviously worth testing close histamine analogues for antagonism to histamine-stimulated gastric secretion.” It was well known that some of the actions of histamine, for example, contraction of smooth muscle, could be blocked by the antihistamines that were ineffective against histamine-induced gastric acid secretion or histamine-induced increase in the rate of beating of the isolated guinea-pig heart. These observations had stimulated Folkow et a1.4 in 1948 to conclude that there are “two receptor substances” for

ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONS IN HISTAMINE ANALOGS. PART 19. 2‐SUBSTITUTED HISTAMINES WITH SELECTIVE H1 AGONISTIC ACTIVITY

Chemischer InformationsdienstVolume 10, Issue 44 Other Subjects ChemInform Abstract: STRUCTURE-ACTIVITY RELATIONS IN HISTAMINE ANALOGS. PART 19. 2-SUBSTITUTED HISTAMINES WITH SELECTIVE H1 AGONISTIC ACTIVITY M. HEPP, M. HEPPSearch for more papers by this authorP. DZIURON, P. DZIURONSearch for more papers by this authorW. SCHUNACK, W. SCHUNACKSearch for more papers by this author M. HEPP, M. HEPPSearch for more papers by this authorP. DZIURON, P. DZIURONSearch for more papers by this authorW. SCHUNACK, W. SCHUNACKSearch for more papers by this author First published: October 30, 1979 https://doi.org/10.1002/chin.197944366Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume10, Issue44October 30, 1979 RelatedInformation

Inhibition of guinea-pig lymphocyte activation by histamine and histamine analogues.

1 The incorporation of [3H]-thymidine into guinea-pig lymphocytes stimulated by a plant lectin (concanavalin A), soluble antigen (tuberculin (P.P.D.)) and syngeneic hepatoma cells, was partially inhibited (50%) by histamine in vitro. 2 The effect of histamine on both mitogen and antigen dose-response curves suggests a non-competitive, probably physiological antagonism. 3 The inhibitory dose range of histamine lay between 10 nM and 30 microM with an ID50 of approximately 400 nM. 4 The potency order for histamine analogues for the inhibition of lymphocyte activation was histamine greater than or equal to 4-methylhistamine greater than 2-methylhistamine greater than 3-methylhistamine. This is in accord with the mediation of the response through an H2-receptor. 5 H2-receptor antagonists reversed the inhibitory effect of histamine in a dose-related manner, but both metiamide and burimamide, in high concentrations, augmented lymphocyte activation in their own right. This precluded the determination of affinity constants and made it impossible to state with certainty that the inhibition of lymphocyte activation by histamine was mediated by an H2-receptor.

Two pharmacologically distinct histamine receptors mediating membrane hyperpolarization on identified neurons of Aplysia californica

Two distinct hyperpolarizing responses are produced when histamine is iontophoretically applied onto the somal membranes of identified neurons within the cerebral ganglion of Aplysia: a biphasic response consisting of a rapid component (< 5sec) usually superimposed upon a slowly developing component; or a monophasic slowly developing response 5–20 sec in duration. The reversal potential values for the fast (typically −65 mV) and the slow (typically −89 mV) responses, and their shift to new values when the external potassium or chloride concentrations were altered, revealed that the fast and slow potentials are produced predominantly by conductance increases to chloride and potassium ions, respectively. The effects of histamine H 1- and H 2-receptor agonists and antagonists were studied to characterize the pharmacological properties of histamine receptors mediating these two ionically dissimilar hyperpolarizing responses. The slow potassium-dependent hyperpolarization could be mimicked by several histamine analogues; the most potent tested were the H 1-receptor agonist, 2-methylhistamine, and the H 2-receptor agonist, 4-methylhistamine. Neither of these agents mimicked the fast chloride-dependent histamine response. The slow potassium-dependent responses induced by histamine or histamine agonists were completely and reversibly blocked by the H 2-receptor antagonist, cimetidine. By contrast, the slow potassium-dependent hyperpolarizations produced by iontophoretically applied acetylcholine or by dopamine to the same neurons were unaffected by cimetidine. Other H 1 and H 2 antagonists tested were either ineffective, or only partially blocked the slow hyperpolarizations in a non-selective manner. The fast chloride-dependent hyperpolarizations were not selectively antagonized by any of the H 1 or H 2 reagents tested, although they were effectively suppressed by tubocurarine and strychnine. These data indicate that two pharmacologically distinct histamine receptors mediate potassium- and chloride-dependent hyperpolarizations in Aplysia neurons. Neither of these receptors, however, could be classified as strictly H 1 or H 2 according to criteria presently used in non-neuronal tissues. The selectivity and reversibility of cimetidine indicate that this particular antihistaminic could be a valuable pharmacological tool for defining putative histaminergic synapses in Aplysia and perhaps other nervous systems.

The use of homologous and hetebologous 125 I-radioligands in the radioimmunoassay of progesterone

Eight homologous and heterologous 125 I-radioligand systems for the radioimmunoassay of progesterone were examined. Using an antiserum raised to 11α-hydroxyprogesterone 11-succinyl-bovine serum albumin, standard curves were set up with the homologous radioligands, 11α-hydroxyprogesterone 11-succinyl-[ 125I]-iodotyramine, -[ 125I]-iodohistamine and -[ 125I]-iodotyrosine methyl ester. Heterologous bridge systems were represented by progesterone-11α-oxycarbonyl-[ 125I]-iodotyrosine methyl ester and 11α-hydroxyprogesterone 11-phthalyl-[ 125I]-iodotyrosine methyl ester, and heterologous site systems by progesterone-3-(O-carboxymethyl)oxime-[ 125I]-iodotyramine, progesterone-12-(O-carboxymethyl) oxime-[ 125 I]-iodotyramine, and progesterone-20-(O-carboxymethyl) oxime-[ 125I]-iodohistamine. The preparation of the steroid derivatives and iodination by a two-phase method are described. The curves obtained from the homologous radioligands were relatively insensitive compared with a tritiated system, with the tyrosine methyl ester derivative providing a more sensitive assay than the corresponding tyramine or histamine analogues. The heterologous bridge systems gave more sensitive curves than the homologous tracers whilst the 3- and 12-(O-carboxymethyl) oxime derivatives of progesterone furnished curves as sensitive as the tritiated reference. Progesterone-20-(O-carboxymethyl)oxime-[ 125I]-iodohistamine was not bound by the antibody.

Structural requirements of imidazole compounds to be inhibitors or activators of histamine methyltransferase: Investigation of histamine analogues and H2-receptor antagonists

The influence of imidazole compounds (histamine analogues and H2-receptor antagonists) and of the specific histamine H2-receptor agonist dimaprit on histamine methyltransferase (HMT) from pig gastric mucosa was investigated.

RESPONSES OF HUMAN SKIN BLOOD VESSELS TO SYNTHETIC HISTAMINE ANALOGUES

The vascular responses of human skin to two synthetic analogues of histamine, 2‐methyl histamine (an H1‐receptor agonist) and 4‐methyl histamine (an H2‐receptor agonist) have been studied in vivo. Both compounds evoked dose‐related erythema, 2‐methyl histamine but not 4‐methyl histamine causing erythema mediated by an axon reflex, thus suggesting that the axon reflex and direct vasodilator action of histamine are due to H1 and H2 actions respectively. The H1‐receptor antagonist chlorpheniramine inhibited erythema due to 2‐methyl histamine. Cimetidine, an H2‐receptor antagonist, had no effect on the reaction to 2‐methyl histamine. In contrast, the erythema reaction to 4‐methyl histamine was suppressed by both cimetidine and chlorpheniramine. Although both histamine analogues caused wealing, this was not dose‐related within the dose range used, and neither chlorpheniramine nor cimetidine caused detectable suppression of wealing responses to either histamine analogue. These results lend further support to the view that human skin blood vessels possess H2 as well as H1 receptors.

Brain histamine N-methyltransferase purification, mechanism of action, and inhibition by drugs

Histamine N-methyltransferase (E.C., 2.1.1.8; HMT) has been purified approximately 200-fold with about 20 per cent yield from guinea pig brain. The purification steps involved centrifugation at 225,000 g for 12hr, calcium phosphate gel adsorption, DEAE-cellulose chromatography and final chromatography on hydroxylapatite. The enzyme obtained is the most highly purified brain HMT so far prepared. It is specific for histamine with a K m of (4.30 ± 0.14) × 10 −5 M; it fails to methylate norepinephrine, serotonin and betazole. a histamine analogue. The kinetics and mechanism of action of histamine N-methyltransferase were investigated. Initial velocity studies at low substrate concentrations suggested that this methyltransferase action proceeded through two half-reactions in a ping pong mechanism with the intermediate formation of a methylated enzyme. This type of mechanism was also supported by results of product inhibition studies, in which methylhistamine was found to inhibit the enzyme competitively with respect to S-adenosylmethionine and noncompetitively with respect to histamine. Several drugs and chemicals were found to inhibit the enzyme; they included mercurial diuretics, antimalarials, antihistaminics, local anesthetics and ethylamine derivatives. The inhibition by each of these compounds, usually at a concentration of 10 −4 M or lower, was competitive with respect to histamine and appeared to be mixed with respect to S-adenosylmethionine. These patterns of inhibition also have a strong support for the ping pong mechanism.

ChemInform Abstract: HISTAMINE ANALOGS, PART 15. Nτ,Nα‐DIMETHYLHISTAMINE

Chemischer InformationsdienstVolume 8, Issue 47 Heterocyclic Compounds ChemInform Abstract: HISTAMINE ANALOGS, PART 15. Nτ,Nα-DIMETHYLHISTAMINE W. SCHUNACK, W. SCHUNACKSearch for more papers by this authorV. STOECK, V. STOECKSearch for more papers by this author W. SCHUNACK, W. SCHUNACKSearch for more papers by this authorV. STOECK, V. STOECKSearch for more papers by this author First published: November 22, 1977 https://doi.org/10.1002/chin.197747201Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume8, Issue47November 22, 1977 RelatedInformation

Histamine Receptors in Esophageal Smooth Muscle of the Opossum

Esophageal smooth muscle was examined for histamine receptors. The effects of histamine, the histamine analogs 4-methylhistamine (4-MH) and 2-(2-pyridyl) ethylamine (PEA), the histamine receptor antagonists mepyramine and metiamide, and the histamine-releasing substance compound 48/80, on lower esophageal sphincter (LES) and esophageal body (EB) smooth muscle of the opossum were studied in a superfused tissue bath. Histamine, PEA, an H1 receptor agonist, and compound 48/80 caused a dose-related increase in LES basal tension and in EB off response amplitude, the threshold for histamine being 6.7 X 10(-8) M and that for PEA being 6.7 X 10(-7) M. In the presence of mepyramine, and H1 receptor antagonist, the effects of histamine and compound 48/80 were reversed to inhibition of both LES basal tension and EB off response amplitude, while the effect of PEA was abolished. Metiamide, an H2 receptor antagonist, did not alter responses to histamine, PEA, or compound 48/80. The H2 receptor agonist 4-methylhistamine caused a reduction of LES tension and EB off response amplitude, but caused an increase in those parameters in the presence of metiamide. A combination of mepyramine and metiamide abolished responses to all agonist drugs. The results indicate that LES and EB smooth muscle contain both excitatory H1 and inhibitory H2 receptors for histamine. Endogenous histamine released from storage sites in LES and EB and exogenous histamine both preferentially activate H1 receptors.

ChemInform Abstract: SYNTHESIS OF HISTAMINE ANALOGS

AbstractAuf verschiedenen Wegen werden die Histamin‐ Analoga (I), (II), (III) und (IV) dargestellt, und ihre biologische Aktivität, speziell ihre Wirkung auf den Blutdruck, die gastrische Sekretion und die Verminderung der nasalen Blutwallung,wird mit der von Histamin verglichen.

CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FORMATION IN GUINEA‐PIG BRAIN SLICES: EFFECT OF H1‐ AND H2‐HISTAMINERGIC AGONISTS

Abstract—A variety of histamine analogs elicit accumulations of radioactive cyclic AMP in guinea‐pig neocortical and hippocampal slices labelled during a prior incubation with [14C]adenine. The H1agonist, 2‐aminoethylthiazole, elicits accumulation of cyclic AMP in neocortical and hippocampal slices both in the absence or presence of adenosine. The presence of adenosine increases the maximum response to 2‐aminoethylthiazole and decreases the EC50 by nearly 10‐fold. In the absence of adenosine the effects of 2‐aminoethylthiazole are antagonized in hippocampal slices by both d‐brompheniramine and metiamide, while in the presence of adenosine only d‐brompheniramine is an effective antagonist. The H2‐agonist, 4‐methylhistamine, elicits a somewhat smaller accumulation of cyclic AMP than does 2‐aminoethylthiazole in both cortical and hippocampal slices. In the presence of adenosine the response to 4‐methylhistamine is enhanced, but is markedly lower than that seen with the combination of adenosine and 2‐aminoethylthiazole. The dose‐response relationship for 4‐methylhistamine in the presence of adenosine appears in hippocampal slices to consist of two components. The response to 4‐methylhistamine in the absence of adenosine is blocked by metiamide, while in the presence of adenosine the response is partially blocked by both H1 and H2‐antagonists. The accumulation of cyclic AMP elicited by histamine is greatly increased by adenosine but the EC50 is not significantly decreased. The results suggest that (i) both H1‐ and H2‐receptors regulate cyclic AMP‐formation in the central nervous system, (ii) the synergism between adenosine and histamine is mediated primarily by interaction with H1‐receptors and (iii) that adenosine greatly increases the affinity of the H1‐receptors for both H1 and H2‐agonists without affecting its affinity for histamine.

ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONS OF HISTAMINE ANALOGS. 9. AMINOBENZYL‐ AND AMINOCYCLOHEXYLMETHYLIMIDAZOLES

Chemischer InformationsdienstVolume 7, Issue 3 Heterocyclic Compounds ChemInform Abstract: STRUCTURE-ACTIVITY RELATIONS OF HISTAMINE ANALOGS. 9. AMINOBENZYL- AND AMINOCYCLOHEXYLMETHYLIMIDAZOLES W. SCHUNACK, W. SCHUNACKSearch for more papers by this author W. SCHUNACK, W. SCHUNACKSearch for more papers by this author First published: January 20, 1976 https://doi.org/10.1002/chin.197603186Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume7, Issue3January 20, 1976 RelatedInformation

A new look at peptic ulcer.

There have been notable advances in knowledge about peptic ulcer recently. Gastrin-producing tumors have been recognized as a rare cause of ulcer, and multiple physiologic defects have been found in duodenal ulcer, including excessive release of gastrin after food intake, increased sensitivity to gastrin, and decreased inhibition by low pH. The tendency of gastric ulcer patients to reflux duodenal contents into the stomach may have pathogenetic significance. Two new classes of drugs strongly inhibit acid secretion in man: chemically modified prostaglandins and histamine analogues which block the action of histamine on acid secretion. Their value in treating ulcer is now being assessed in clinical trials. A new operation for duodenal ulcer shows promise: only those vagal fibers innervating the acid-secreting part of the stomach are severed, thus obviating the need for a drainage procedure and decreasing some of the undersirable side effects of earlier operations.

Synthesis of Histamine Analogs

AbstractNineteen histamine analogs were synthesized, and their biological actions were compared to those of histamine in blood pressure, gastric secretion, and nasal decongestant screens. The analogs include N‐substituted 4‐aminoethylimidazoles, N‐substituted 2‐pyridylethylamines, 2‐pyridylcyclohexylamines, and 2‐pyridylcyclopropylcarbamates. None of the compounds showed appreciable histamine agonist or antagonist properties.