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PubMed1983

Histamine receptor blockade (H2) versus inhibition of histamine synthesis in stress ulceration in rats.

Cold and restraint stress in rats induced gastric mucosa lesions, increased gastric mucosa histidine decarboxylase activity and elevated hypothalamic content. Cimetidine did not modify the biochemical effects induced by stress but partially protected against gastric ulceration. alpha-Fluoromethyl histidine inhibited the increase of histidine decarboxylase activity in the gastric mucosa, inhibited the rise of hypothalamic histamine content and decreased the incidence of gastric lesions to the same extent as did cimetidine.

Animals↗
PubMed2005

Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists.

In search for a new lead of non-imidazole histamine H3-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4-n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]piperazine were prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs the thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA2 = 7.25 (its oxazole analogue (4g) showed pA2 = 6.9). The structure-activity relationships for compounds with various positions of the nitrogen in the benzene ring for the thiazoles compared with oxazoles are discussed.

Animals↗
PubMed2001

Comparison of intra-accumbens injection of histamine with histamine H1-receptor antagonist chlorpheniramine in effects on reinforcement and memory parameters.

Histaminergic neurons are located exclusively in the tuberomammillary nuclei (TM) of the hypothalamus from where they project to many regions of the brain including the basal ganglia. Earlier experiments led to the hypothesis that neuronal histamine (HA), particularly in relation to the H1 receptor, has an inhibitory role in learning and reward-related processes. Based on this premise, the objective of the present study was to compare HA with the H1-receptor antagonist d-chlorpheniramine (CPR) in effects on reinforcement and memory parameters after injection into different subregions of the rat nucleus accumbens (NAcc). In the first experiment, mnemoactive effects of CPR (0.1-10 microg) were assessed after injection into the caudal or rostral part of the NAcc with the one-trial uphill avoidance task as a measure of learning. The data show that intra-NAcc injection of CPR (10 microg) facilitated retention of the task, when the compound was administered immediately after training. This effect was evident only when CPR was administered into the caudal-shell but not into the rostral pole of the NAcc providing evidence for anatomical specificity of the intra-NAcc induced promotion of memory. In the second experiment, possible mnemonic and reinforcing effects of HA (0.001-1 microg) were gauged after injection of the amine into the caudal NAcc, using post-trial application in the uphill avoidance task to assess effects on learning and place preference as an index of reinforcing properties. The data show that caudal-NAcc injection of HA (0.1 microg) improved retention of the avoidance task and produced place preference indicative of a reinforcing action. The finding that intra-NAcc injection of HA can facilitate learning and has reinforcing effects is at variance with the proposed inhibitory nature of neuronal HA in reward-related processes. Thus, the disinhibition of reinforcement and facilitation of learning found earlier after partial destruction of TM-intrinsic neurons might not necessarily be related to a lesion-induced reduction of the HAergic tone. The observation that CPR has behavioral effects quite similar to HA suggests that the mnemoactive and reinforcing action of this compound might involve pharmacodynamic aspects beyond its antagonistic activity at H1-receptive sites.

Animals↗
PubMed1995

A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist.

Employing classical conformational analysis on a known H3 agonist, (R)-alpha-methylhistamine (1), a series of conformationally constrained H3 agonists were proposed and synthesized. Pyrrolidine (+/-)-4a, a compound proposed to mimic the anti-conformation of (R)-alpha-methylhistamine (1), was found to be a potent and selective H3 agonist. The pyrrolidine (+/-)-4a was resolved, and its (+) enantiomer, immepyr [(+)-4a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 550) than (R)-alpha-methylhistamine (1) (H3/H1 ratio = 17), the standard H3 agonist. In fact, no evidence of H1 activity was detected at doses of immepyr [(+)-4a] as high as 100 mg/kg i.v. This pyrrolidine, immepyr [(2R,3S)-(+)-4a], represents, to our knowledge, the first reported cyclic, conformationally restricted analog of histamine to possess selective in vivo H3 agonist activity.

Histamine↗
PubMed1994

Structures of histamine H1-receptor antagonists derived from the cimetidine group of histamine H2-receptor antagonists.

The crystal and molecular structures of ten compounds with strong structural resemblances to the cimetidine group of histamine H2-receptor antagonists, but exhibiting selective H1-receptor antagonist activity, (1)-(7), or H1 and H2 activity (8)-(10), have been determined: (1) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-5- (6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrobromide (temalastine), C21H27BrN5O3+.3Br-, M(r) = 685.09, triclinic, P1, a = 6.314 (2), b = 11.192 (2), c = 19.441 (5) A, alpha = 102.47 (2), beta = 92.77 (2), gamma = 103.28 (2) degrees, V = 1298.51 A3, Z = 2, Dx = 1.75 g cm-3, mu = 61.6 cm-1, F(000) = 672, R = 2.93% for 3208 independent reflexions. (2) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4-pyrimidone, C14H19BrN4O2, M(r) = 355.23, monoclinic, I2/a, a = 16.359 (3), b = 10.469 (6), c = 18.339 (4) A, beta = 90.90 (2) degrees, V = 3140.49 A3, Z = 8, Dx = 1.503 g cm-3, mu = 26.0 cm-1, F(000) = 1176, R = 4.2% for 1872 independent reflexions. (3) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- amino-1,2,5-thiadiazole-1-oxide, C12H16BrN5OS, M(r) = 358.26, triclinic, P1, a = 14.295 (2), b = 12.447 (2), c = 9.917 (2) A, alpha = 95.77 (2), beta = 113.86 (2), gamma = 106.91 (1) degrees, V = 1495.18 A3, Z = 4, Dx = 1.59 g cm-3, mu = 50.96 cm-1, F(000) = 728, R = 5.98% for 5674 independent reflexions. (4) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- benzylamino-1,2,5-thiadiazole-1-oxide, C19H22BrN5OS, M(r) = 448.38, monoclinic, P2(1)/c, a = 36.293 (7), b = 4.826 (2), c = 11.528 (3) A, beta = 96.91 (2) degrees, V = 2004.27 A3, Z = 4, Dx = 1.49 g cm-3, mu = 39.2 cm-1, F(000) = 920, R = 12.1% for 1945 independent reflexions. (5) 2-[3-(N-Benzyl-N-2- pyridylamino)propylamino]-4-pyrimidone, C19H21N5O, M(r) = 335.4, orthorhombic, Pbna, a = 7.082 (1), b = 19.889 (3), c = 24.899 (3) A, V = 3507.16 A3, Z = 8, Dx = 1.27 g cm-3, mu = 6.24 cm-1, F(000) = 1424, R = 4.05% from 2470 independent reflexions. (6) 3-[3-(N-4-Fluorobenzyl-N-2- pyridylamino)propylamino]-4-ethylamino-1,2,5-thiadiazole-1-oxide, C19H23FN6OS, M(r) = 402.5, monoclinic, P2(1)/n, a = 6.686 (2), b = 14.717 (3), c = 20.850 (5) A, beta = 97.83 (2) degrees, V = 2032.47 A3, Z = 4, Dx = 1.32 g cm-3, mu = 16.41 cm-1, F(000) = 848, R = 8.5% from 2484 independent reflexions. (7) 5-(6-Methyl-3-pyridylmethyl)-2-[3-(5,6,7,8-tetrahydro-8- quinolyl)propylamino]-4-pyrimidone, C23H29N5O2, M(r) = 407.5, monoclinic, P2(1)/c, a = 14.966 (2), b = 16.075 (2), c = 9.1608 (9) A, beta = 99.158 (8) degrees, V = 2175.83 A3, Z = 4, Dx = 1.24 g cm-3, mu = 6.19 cm-1; F(000) = 872, R = 5.3% from 2784 independent reflexions. (8) 2-(4-Phenylbutylamino)-5-(3-pyridyl-methyl)-4-pyrimidone, C20H26N4O3, M(r) = 370.5, monoclinic, P2(1)/c, a = 8.040 (4), b = 21.279 (4), c = 11.404 (2) A, beta = 92.08 (5) degrees, V = 1949.68 A3, Z = 4, Dx = 1.26 g cm-3, mu = 0.93 cm-1, F(000) = 792, R = 4.05% from 3816 independent reflexions.(ABSTRACT TRUNCATED AT 400 WORDS)

Cimetidine↗
PubMed1990

Histamine lipolysis II: effects of histamine and related compounds on membrane potentials of rat adipocytes.

The effects of histamine (Hi) and related compounds on rat mesenterial adipocytes were investigated using electrophysiological techniques. Hi caused a concentration-related depolarization and significant effect was observed at concentrations higher than 5 x 10(-6) M. Effective membrane resistance was also decreased by Hi. The H1-agonists 2-methylHi and 2-thiazolylethylamine caused no depolarization even at a concentration of 5 x 10(-4) M, but the H2-agonists, 4-methylHi and impromidine decreased resting membrane potentials. While 4-methylHi was less potent than Hi, impromidine was more potent. The H1-antagonists diphenhydramine and pyrilamine did not affect Hi-induced depolarization. However, H2-antagonists like cimetidine and ranitidine caused a significant inhibition even at a concentration of 10(-6) M. As in the case of isoproterenol, the decrease in resting membrane potentials induced by Hi was significantly potentiated by theophylline. Dibutyryl cyclic AMP treatment and intracellular application of cyclic AMP also caused a marked depolarization.

Adipose Tissue↗
PubMed1988

[Impromidine-analogous guanidines: synthesis and activity at the histamine H2-receptor. 29. Histamine analogs].

19 impromidine analogous guanidines were synthetized by acid hydrolysis of the corresponding N-cyanoguanidines. The guanidines were tested on the isolated spontaneously beating guinea-pig atrium for histamine H2-receptor affinity. Lengthening the ethyl chain of cysteamine by one methylene group leads to partial agonists of decreased activity. Impromidine congeners containing a branched cimetidine side chain prove to be potent H2-agonists with maximal or near maximal response. Affinity ratios in favour of the (R)-configurated enantiomers are moderate but clearly significant. The interaction between the affinity contributing moiety and the complementary receptor area shows a lower degree of stereoselectivity than does the efficacy contributing (imidazole-4-yl)propyl substituent of impromidine and sopromidine, respectively. Homoisohistamine derivatives dramatically lose both efficacy and affinity.

Animals↗
PubMed1999

Non-imidazole histamine H3 ligands, Part 2: New 2-substituted benzothiazoles as histamine H3 antagonists.

New, non-imidazole histamine H3 receptor antagonists were prepared and in vitro tested as H3 receptor antagonists measured as the electrically evoked contraction of the guinea-pig jejunum. The 2-(1-piperidinyl)- and 2-(1-pyrrolidinyl)benzothiazoles show no or very poor activity; 2-[1-(4-amino)piperidinyl]- and 2-(1,2-ethanediamino)- and 2-(1,3-propanediamino)derivatives of benzothiazole possess weak activity at H3 receptors, whereas 2-(4-piperidinyl)benzothiazoles and 2-[1-(4-piperazinyl)]benzothiazoles show moderate to good activity. Lipophilic and not-too-bulky substituents like n-propyl attached to the nitrogen at the piperazine or piperidine ring lead to potent H3 receptor antagonists with pA2 values ranging from 7.0 to 7.2. The structure-activity relationships for different substitution patterns are discussed.

Animals↗
PubMed1983

Histamine release into tracheal lumen and bronchial reactivity. The histamine liberation of proteolytic enzymes in the tracheal lumen in relation to the bronchomotoric reactivity.

The influence of tracheal lavage in a restricted area, with a proteolytic enzyme (Pronase) on the bronchial response to challenge with ACH and AE was studied in 15 dogs. Histamine concentrations measured in the tracheal liquid after lavage with Pronase were smaller than the values after tracheal lavage with allergen. Airway response to ACH inhalation was significantly increased after tracheal lavage with Pronase. Effects of proteolytic enzymes and allergens on the tracheal wall are compared. Allergens and proteolytic enzymes evidence a different mode of action in increasing reactivity of peripheral airways.

Allergens↗
PubMed1977

The role of histamine in wound healing I. The effect of high doses of histamine on collagen and glycosoaminoglycan content in wounds.

The effect of high doses of histamine (Hi) on collagen and glycosoaminoglycan (GAG) content in skin wounds of rats was studied on days 1, 3, 5, 10 and 14 after wounding. Injection of high doses of Hi into the wounded area inhibited colagen production, collagen polymerization and GAG synthesis; levels of chondroitin sulphates (chondroitin-4,6-sulphate and dermatan sulphate) and hyaluronic acid were decreased.

Animals↗
PubMed1978

Phosphopyridoxal cyclic compounds with histamine and histidine. 6: The formation of phosphopyridoxal cyclic compounds with histamine and histidine in the presence of biological material.

We have studied the dynamics of cyclic compound formation between histamine or histidine and pyridoxal 5'-phosphate (Hi-PLP or His-PLP) in incubates of rat gastric mucosa histidine decarboxylase (HD), rat intestinal diamine oxidase (DAO) or homogenates of either rat liver, intestine or gastric mucosa. For gastric mucosa HD, liver and gastric mucosa homogenates, the rate of cyclization was slightly decreased; however, the rate was significantly inhibited with intestinal DAO or intestinal homogenate. Binding of PLP by tissue components was measured; free PLP was bound abundantly by rat intestinal DAO and by rat intestinal homogenate. A possible mechanism by which intestinal tissues inhibit cyclic compound formation is discussed.

Amine Oxidase (Copper-Containing)↗
PubMed1978

Phosphopyridoxal cyclic compounds with histamine and histidine. 7: The properties of pyridoxal and phosphopyridoxal cyclic compounds with histamine and histidine.

Cyclic compounds synthesized from histamine (Hi) or histidine (His) with pyridoxal (PL)--[Hi-PL, His-PL] and Hi or His with pyridoxal 5'-phosphate (PLP)--[Hi-PLP, His-PLP] were tested for stability in buffer, acid and base solutions, crude homogenates of various tissues and in the presence of enzymes which metabolize Hi or His. The cyclic pyridoxal compounds were stable in all experimental conditions, whereas phosphopyridoxal cyclic products were degraded by rat intestinal DAO and rat intestine homogenate, apparently enzymatically. In acidic and basic solutions changes in migration velocity and u.v. absorption spectrum occur. The characteristic fluorescence of these cyclic compounds is described.

Animals↗
PubMed1984

Histamine turnover in the brain of different mammalian species: implications for neuronal histamine half-life.

The turnover of neuronal histamine (HA) in nine brain regions and the spinal cord of the guinea pig and the mouse was estimated and the values obtained were compared with data previously obtained in rats. The size of the neuronal HA pool was determined from the decrease in HA content, as induced by (S)-alpha-fluoro-methylhistidine (alpha-FMH), a suicide inhibitor of histidine decarboxylase. The ratios of neuronal HA to the total differed with the brain region. Pargyline hydrochloride increased the tele-methylhistamine (t-MH) levels linearly up to 2 h after administration in both the guinea pig and the mouse whole brain. Regional differences in the turnover rate of neuronal HA, calculated from the pargyline-induced accumulation of t-MH, as well as in the size of the neuronal HA pool, were more marked in the mouse than in the guinea pig brain. The hypothalamus showed the highest rate in both species. There was a good correlation between the steady-state t-MH levels and the turnover rate in different brain regions. Neither the elevation of the t-MH levels by pargyline nor the reduction of HA by alpha-FMH was observed in the spinal cord, thereby suggesting that the HA present in this region is of mast cell origin. The half-life of neuronal HA in different brain regions was in the range of 13-38 min for the mouse and 24-37 min for the guinea pig, except for HA from the guinea pig hypothalamus, which had an extraordinarily long value of 87 min. These results suggest that there are species differences in the function of the brain histaminergic system.

Animals↗
PubMed1989

Histamine turnover in the rat hypothalamic nuclei estimated from alpha-fluoromethylhistidine-induced histamine decrease.

The turnover rates, rate constants and half-life values of neuronal histamine (HA) in 10 nuclei of the rat hypothalamus were estimated from the depletion of HA induced by alpha-fluoromethylhistidine (alpha-FMH: 100 mg/kg, i.p.), a specific inhibitor of histidine decarboxylase, on the presumption that alpha-FMH depletable HA pools represent neuronal ones. Marked variation in the HA turnover rates were observed among the hypothalamic nuclei, ranging from 5.7 to 19.5 pmole/mg protein/hr.

Animals↗
PubMed2006

Recent advances in molecular pharmacology of the histamine systems: regulation of histamine H1 receptor signaling by changing its expression level.

Histamine H1 receptor (H1R) signaling is regulated by changing its expression level. Two mechanisms are involved in this regulation. One is down-regulation through receptor desensitization. Receptor phosphorylation seemed crucial because stimulation of the mutant H1R lacking five putative phosphorylation sites did not show down-regulation. The phosphorylation level of the mutant receptor was much smaller than that of the wild type ones by several protein kinases. The other is up-regulation through activation of receptor gene expression. Protein kinase C (PKC) signaling was suggested to be involved in this up-regulation. Regulation of H1R expression level was mediated not only through H1R but also autonomic nerve receptors. Stimulation of M3 muscarinic receptors (M3R) induced both down-regulation and up-regulation of H1R. Down-regulation of M3R-mediated H1R seemed not to be mediated by PKC activation, although PKC activation induced H1R phosphorylation. Elevation of H1R expression was induced by the stimulation of M3Rs. PKC was suggested to be involved in this up-regulation. Stimulation of beta2-adrenergic receptors induced H1R down-regulation through several mechanisms. One of them is enhanced receptor degradation after desensitization and another is suppression of receptor synthesis that includes the suppression of receptor gene expression and enhanced degradation of the receptor mRNA. Protein kinase A was suggested to be involved in enhanced degradation and the activation of the receptor gene expression. Elevation of both H1R expression and its mRNA was observed in nasal mucosa of nasal hypersensitivity allergy model rat after toluene diisocyanate provocation. These results suggest that activation of H1R gene expression plays an important patho-physiological role in allergy. Elevation of the mRNA was partially but significantly suppressed by antihistamines.

Animals↗
PubMed2005

Addition of histamine to interleukin 2 treatment augments type 1 T-cell responses in patients with melanoma in vivo: immunologic results from a randomized clinical trial of interleukin 2 with or without histamine (MP 104).

PURPOSE: Preclinical investigations suggest that histamine dihydrochloride (HDC) protects T cells and natural killer cells from inhibition by monocyte-derived reactive oxygen metabolites and synergizes with interleukin (IL) 2 in inducing T-cell activation. Here, we investigate whether this mechanism is operational in patients with melanoma treated with HDC as an adjunct to IL-2. EXPERIMENTAL DESIGN: Melanoma patients having liver metastases were treated with IL-2 with or without HDC within a randomized, multicenter, phase III trial. The effect of HDC on type 1 and type 2 T-cell cytokine production was investigated in peripheral blood samples from 19 patients with the use of intracellular cytokine flow cytometry. Melanoma-specific T-cell responses were analyzed in eight HLA-A2-positive patients. RESULTS: Frequencies of CD3+ T cells producing IFN-gamma (type 1 T cells) in response to phorbol myristate acetate/ionomycin increased (median, 1.8-fold) in patients receiving IL-2 plus HDC but not in those receiving IL-2 alone (P < 0.01 for comparison between arms). In contrast, the number of IL-13-producing type 2 T cells that increased in patients after treatment with IL-2 was not modulated by HDC. Melanoma- and tyrosinase-specific IFN-gamma and IL-13-producing T cells were detected in two of four HLA-A2-positive patients with melanoma following treatment with HDC + IL-2. CONCLUSIONS: Treatment of patients with stage IV melanoma with HDC in combination with IL-2 increases type 1 T-cell responses and may promote induction of melanoma-specific T cells. These effects are of relevance for tumor immunotherapy and provide a potential mechanism for the clinical efficacy of HDC added to IL-2.

CD3 Complex↗
PubMedDate not supplied

Depolarisation-evoked release of dopamine and histamine from brain tissue and studies on presynaptic dopamine-histamine interaction.

The inhibitory dopamine (DA) presynaptic receptors which are localized on dopaminergic nerve terminals, so called DA autoreceptors, modulate the neurotransmitter release and synthesis by means of negative feedback mechanism. DA agonists decrease and DA antagonists facilitate stimulation-evoked calcium-dependent DA release. DA auto-receptors correspond to D2-subtype DA receptors. They are chemically stereoselective and their sensitivity change when exposed chronically to DA receptor blockers. It is thought that presynaptic inhibitory DA autoreceptors play crucial role in physiological regulation of the neurotransmitter release from nerve terminals. Accumulating evidence indicates that, in analogy to the dopaminergic system in the brain, histaminergic neurons take up radioactive histamine (HI), and when exposed to depolarizing stimuli, they release the neurotransmitter in a calcium-dependent manner. Recent experiments showed that exogenous HI is able to inhibit potassium-stimulated release of 3H-HI from brain slices prelabelled previously with 3H-1-histidine. A suggestion has been put forward that HI release from nerve terminals may be autoregulated by a new class of HI receptors, so called H3 autoreceptors (which are pharmacologically different from both H1 and H2 receptors), in a way very similar to dopaminergic autoregulatory mechanisms. Literature data and our own findings suggest the existence of HI receptors localized on the striatal dopaminergic nerve terminals, through which HI could modulate depolarization-evoked DA release. The inability of DA agonist (apomorphine) and DA antagonists (haloperidol and s-sulpiride) to affect the electrically-evoked 3H-HI release from the rabbit hypothalamic slices suggests that there are no DA presynaptic receptors modulating HI release.

Animals↗
PubMed1983

Method for detection of antibody against low molecular weight antigen (hapten)--production and detection of antibody against histamine H2 receptor of antibody against histamine H2 receptor antagonist "Famotidine".

Antibodies against histamine H2-receptor antagonist "Famotidine (FAMO)", molecular weight 337, chemical name; N-sulfamoyl-3-(2-guanidinothiazol-4-ylmethylthio) propionamide, were produced by subcutaneously injecting rabbits with an albumin and FAMO conjugate covalently bound with 1-ethyl-3-(3-dimethyl-amino-propyl) carbodiimide (ECDI). Two new detection systems for antibody titration were developed and employed. In one method, the antigen FAMO was tagged to sheep red blood cells (SRBC) and analysed qualitatively by a fluorescence activated cell sorter (FACS) using a second fluorescence isothiocyanate (FITC) labeled antibody. In the other method, CH-Sepharose beads were employed in place of SRBC and Horse Radish Peroxidase (HRP) was labeled to the second antibody instead of FITC used in the former method. HRP of the immune complex was colorimetrically measured with DAB-H2O2 to analyse the fine antibody titer. These high sensitive detection methods revealed the existence of IgG type of FAMO antibody. The detection sensitive detection methods revealed the existence of IgG type of FAMO antibody. The detection sensitivity was approximately 50 to 100 times higher in the later method with HRP than in the former. Furthermore these two methods could be deemed to be a good model system for a receptor assay.

Animals↗