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Armin Buschauer - One of the best experts on this subject based on the ideXlab platform.
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abolishing dopamine d2long d3 Receptor affinity of subtype selective carbamoylguanidine type Histamine H2 Receptor agonists
Journal of Medicinal Chemistry, 2021Co-Authors: Katharina Tropmann, Armin Buschauer, Steffen Pockes, Merlin Bresinsky, Lisa Forster, Denise Monnich, Hansjoachim Wittmann, Harald Hubner, Peter GmeinerAbstract:3-(2-Amino-4-methylthiazol-5-yl)propyl-substituted carbamoylguanidines are potent, subtype-selective Histamine H2 Receptor (H2R) agonists, but their applicability as pharmacological tools to elucidate the largely unknown H2R functions in the central nervous system (CNS) is compromised by their concomitant high affinity toward dopamine D2-like Receptors (especially to the D3R). To improve the selectivity, a series of novel carbamoylguanidine-type ligands containing various heterocycles, spacers, and side residues were rationally designed, synthesized, and tested in binding and/or functional assays at H1-4 and D2long/3 Receptors. This study revealed a couple of selective candidates (among others 31 and 47), and the most promising ones were screened at several off-target Receptors, showing good selectivities. Docking studies suggest that the amino acid residues (3.28, 3.32, E2.49, E2.51, 5.42, and 7.35) are responsible for the different affinities at the H2- and D2long/3-Receptors. These results provide a solid base for the exploration of the H2R functions in the brain in further studies.
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dimeric carbamoylguanidine type Histamine H2 Receptor ligands a new class of potent and selective agonists
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Nicole Kagermeier, Roland Seifert, Günther Bernhardt, Paul Baumeister, Kristin Werner, Max Keller, Armin BuschauerAbstract:The bioisosteric replacement of the acylguanidine moieties in dimeric Histamine H2 Receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of Histamine when studied in [35S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over Histamine Receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes.
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3h ur de257 development of a tritium labeled squaramide type selective Histamine H2 Receptor antagonist
ChemMedChem, 2015Co-Authors: Paul Baumeister, Sigurd Elz, Günther Bernhardt, Daniela Erdmann, Sabrina Biselli, Nicole Kagermeier, Armin BuschauerAbstract:A series of new piperidinomethylphenoxypropylamine-type Histamine H2 Receptor (H2R) antagonists with different substituted “urea equivalents” was synthesized and characterized in functional in vitro assays. N-6-(3,4-Dioxo-2-{3-3-(piperidin-1-ylmethyl)phenoxy]-propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide (3HUR-DE257, 24b) was selected for radiosynthesis. The radioligand (specific activity: 63 Ci • mmol-1) had a high affinity for the human, the rat and the guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 (24a) revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: >10000 nM, hH2R: 28 nM, hH3R: 3800 nM, hH4R: >10000 nM). Regardless of insurmountable antagonism, characteristic for this class of compounds depending on the type of functional assay, and of rebinding of 24b to the H2R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2R affinities in competition binding assays.
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the bivalent ligand approach leads to highly potent and selective acylguanidine type Histamine H2 Receptor agonists
Journal of Medicinal Chemistry, 2012Co-Authors: Tobias Birnkammer, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt, Nicole Kagermeier, Anja Spickenreither, Irena Brunskole, Miroslaw Lopuch, Armin BuschauerAbstract:Bivalent Histamine H2 Receptor (H2R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by NG-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H2R agonism in GTPase and [35S]GTPγS binding assays at guinea pig (gp) and human (h) H2R-GsαS fusion proteins including various H2R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H1, H3, and H4 Receptors. The bivalent ligands are H2R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than Histamine at the gpH2R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H2R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH2 groups) to simultaneously occupy two orth...
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NG‐Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H2 Receptor Agonists
ChemMedChem, 2009Co-Authors: Anja Kraus, Prasanta Ghorai, Tobias Birnkammer, David Schnell, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt, Armin BuschauerAbstract:The bioisosteric replacement of the guanidino group in arpromidine-like Histamine H2 Receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and penetration across the blood brain barrier. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropyl-guanidines for the H2R is poor, in particular versus Histamine H3 (H3R) and H4 Receptors (H4R). This drawback appears to depend on the "privileged" imidazolylpropylguanidine structure. The 2-amino-4-methylthiazol-5-yl moiety is a bioisostere of the imidazole ring in the moderately potent H2R selective Histamine analogue amthamine. This approach was successfully applied to acylguanidine-type H2R agonists. The aminothiazoles are nearly equipotent with the corresponding imidazoles as H2R agonists. Compared to Histamine, the potency is increased up to 40-fold on the guinea pig right atrium and up to 125- and 280-fold, respectively, in GTPase assays at human and guinea pig H2R-GsαS fusion proteins expressed in Sf9 insect cells. Docking studies on H2R models support the hypothesis that 2-aminothiazolyl and imidazolyl derivatives interact with H2Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H1, H3 and H4 Receptors. Moreover, unlike amthamine, the 4-methyl group does not significantly contribute to the H2R agonism of N(G)-acylated 2-amino-4-methylthiazol-5-ylpropylguanidines.
Koji Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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protective effect of lafutidine a Histamine H2 Receptor antagonist against loxoprofen induced small intestinal lesions in rats
Journal of Gastroenterology and Hepatology, 2010Co-Authors: Kikuko Amagase, Akimu Ochi, Tetsuya Sugihara, Shinichi Kato, Koji TakeuchiAbstract:Background and Aims: We examined the effect of lafutidine, a Histamine H2 Receptor antagonist with a mucosal protective action mediated by capsaicin-sensitive sensory neurons (CSN), on intestinal lesions produced by loxoprofen administration in rats. Methods: Animals were given loxoprofen (10–100 mg/kg p.o.) and killed 24 h later. Lafutidine (10 and 30 mg/kg), cimetidine (100 mg/kg) or famotidine (30 mg/kg) was given twice p.o. at 0.5 h before and 6 h after loxoprofen. Omeprazole (100 mg/kg) was given p.o. once 0.5 h before. Ampicillin (800 mg/kg) was given p.o. twice at 24 h and 0.5 h before loxoprofen, while 16,16-dimethyl prostaglandin E2 (dmPGE2; 0.01 mg/kg) was given i.v. twice at 5 min before and 6 h after. Results: Loxoprofen dose-dependently produced hemorrhagic lesions in the small intestine, accompanied by invasion of enterobacteria and increased inducible nitric oxide synthase (iNOS) expression as well as myeloperoxidase activity in the mucosa. The ulcerogenic response to loxoprofen (60 mg/kg) was significantly prevented by lafutidine (30 mg/kg), similar to dmPGE2 and ampicillin, and the effect of lafutidine was totally attenuated by ablation of CSN. Neither cimetidine, famotidine nor omeprazole had a significant effect against these lesions. Lafutidine alone increased mucus secretion and reverted the decreased mucus response to loxoprofen, resulting in suppression of bacterial invasion and iNOS expression. In addition, loxoprofen downregulated Muc2 expression, and this response was totally reversed by lafutidine mediated by CSN. Conclusion: Lafutidine protects the small intestine against loxoprofen-induced lesions, essentially mediated by the CSN, and this effect may be functionally associated with increased Muc2 expression/mucus secretion, an important factor in the suppression of bacterial invasion.
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impairment by 5 fluorouracil of the healing of gastric lesions in rats effect of lafutidine a Histamine H2 Receptor antagonist mediated by capsaicin sensitive afferent neurons
Digestive Diseases and Sciences, 2009Co-Authors: Yukiko Murashima, Kikuko Amagase, Tohru Kotani, Shusaku Hayashi, Yoshino Komatsu, Akari Nakagiri, Koji TakeuchiAbstract:We investigated the influence of 5-fluorouracil (5-FU), an anti-tumor agent, on the healing of gastric lesions generated by 0.6 M HCl in rats and the effect of lafutidine, a Histamine H2 Receptor antagonist, on the impaired healing. Animals fasted for 18 h were given 1 ml of 0.6 M HCl p.o., fed normally from 1 h later, and killed 1–96 h thereafter. 5-FU was given i.v. twice, 1 h and 24 h after the HCl. The gastric lesions healed spontaneously within 96 h. Although it decreased acid secretion, 5-FU markedly delayed the healing. Lafutidine, but not cimetidine, given p.o. immediately after each dosing of 5-FU significantly reversed the delay in healing by 5-FU, and this effect was attenuated by the chemical ablation of capsaicin-sensitive afferent neurons. Capsaicin also significantly reversed the delay in healing. The mucosal application of 50 mM HCl did not affect gastric mucosal blood flow (GMBF) in the normal stomach, but significantly increased it in the stomach damaged by 0.6 M HCl. The increases in GMBF were attenuated by 5-FU; however, the co-administration of lafutidine significantly restored the response. In addition, 5-FU inhibited both cell proliferation and migration in rat gastric epithelial cells (RGM1) in vitro. These results suggest that 5-FU delayed the healing of gastric lesions generated by 0.6 M HCl, probably through the inhibition of cell migration and proliferation, as well as the impairment of GMBF, and lafutidine reversed the delay in healing, mainly through the amelioration of the GMBF response mediated by capsaicin-sensitive afferent neurons.
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protective effect of lafutidine a novel Histamine H2 Receptor antagonist on dextran sulfate sodium induced colonic inflammation through capsaicin sensitive afferent neurons in rats
Digestive Diseases and Sciences, 2004Co-Authors: Mitsuaki Okayama, Shinichi Kato, Ryoichi Tsubouchi, Koji TakeuchiAbstract:Lafutidine, a Histamine H2-Receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS) -induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.
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effect of lafutidine a Histamine H2 Receptor antagonist on gastric mucosal blood flow and duodenal hco3 secretion in rats relation to capsaicin sensitive afferent neurons
Digestive Diseases and Sciences, 2002Co-Authors: Hiroshi Mimaki, Shinichi Kato, Shigeru Kagawa, Tsutumi Satoshi, Kazuhiro Kohama, Koji TakeuchiAbstract:Lafutidine is a new type of antiulcer drug, possessing both an antisecretory effect, exerted via a blockade of the Histamine H2 Receptor, and gastroprotective activity, mediated by capsaicin-sensitive afferent nerves (CSN). In the present study, we examined the effect of lafutidine on gastric mucosal blood flow (GMBF) and duodenal HCO3− secretion (DAS) under basal and acid-stimulated conditions in rats. Under urethane anesthesia, GMBF was measured using a laser Doppler flowmeter in a chambered stomach before and after exposure to 20 mM taurocholate (TC) plus 50 mM HCl, while DAS was measured in a proximal duodenal loop before and after mucosal acidification (10 mM HCl for 10 min) by titrating the perfusate at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Lafutidine given intraperitoneally affected neither GMBF nor DAS under basal conditions, but augmented an increase in both GMBF and DAS induced by mucosal acidification. Although the acid-induced GMBF and DAS responses were significantly mitigated by both indomethacin and sensory deafferentation but not by ruthenium red (RT), the vanilloid Receptor (VR)-1 antagonist, the responses were preserved in lafutidine-treated animals, even in the presence of indomethacin. Both GMBF and DAS were significantly increased by local application of capsaicin, the responses being attenuated by indomethacin and RT as well as sensory deafferentation. Lafutidine augmented the GMBF and DAS responses to capsaicin and preserved the responses, even in the presence of indomethacin. Capsaicin evoked an increase in [Ca2+]i in rat VR1-transfected HEK293 cells, while lafutidine had no effect by itself on [Ca2+]i in these cells and did not affect the increase in [Ca2+]i evoked by capsaicin. In conclusion, these results suggest that lafutidine mimics endogenous effects of prostaglandins to augment the GMBF and DAS responses to acid or capsaicin, probably by sensitizing CSN through an unknown site other than VR1. The luminal H+ itself is not a ligand for the RT-sensitive site of VR1 but plays a modulator role in the CSN-mediated physiological responses.
Roland Seifert - One of the best experts on this subject based on the ideXlab platform.
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dimeric carbamoylguanidine type Histamine H2 Receptor ligands a new class of potent and selective agonists
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Nicole Kagermeier, Roland Seifert, Günther Bernhardt, Paul Baumeister, Kristin Werner, Max Keller, Armin BuschauerAbstract:The bioisosteric replacement of the acylguanidine moieties in dimeric Histamine H2 Receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of Histamine when studied in [35S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over Histamine Receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes.
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the bivalent ligand approach leads to highly potent and selective acylguanidine type Histamine H2 Receptor agonists
Journal of Medicinal Chemistry, 2012Co-Authors: Tobias Birnkammer, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt, Nicole Kagermeier, Anja Spickenreither, Irena Brunskole, Miroslaw Lopuch, Armin BuschauerAbstract:Bivalent Histamine H2 Receptor (H2R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by NG-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H2R agonism in GTPase and [35S]GTPγS binding assays at guinea pig (gp) and human (h) H2R-GsαS fusion proteins including various H2R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H1, H3, and H4 Receptors. The bivalent ligands are H2R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than Histamine at the gpH2R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H2R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH2 groups) to simultaneously occupy two orth...
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NG‐Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H2 Receptor Agonists
ChemMedChem, 2009Co-Authors: Anja Kraus, Prasanta Ghorai, Tobias Birnkammer, David Schnell, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt, Armin BuschauerAbstract:The bioisosteric replacement of the guanidino group in arpromidine-like Histamine H2 Receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and penetration across the blood brain barrier. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropyl-guanidines for the H2R is poor, in particular versus Histamine H3 (H3R) and H4 Receptors (H4R). This drawback appears to depend on the "privileged" imidazolylpropylguanidine structure. The 2-amino-4-methylthiazol-5-yl moiety is a bioisostere of the imidazole ring in the moderately potent H2R selective Histamine analogue amthamine. This approach was successfully applied to acylguanidine-type H2R agonists. The aminothiazoles are nearly equipotent with the corresponding imidazoles as H2R agonists. Compared to Histamine, the potency is increased up to 40-fold on the guinea pig right atrium and up to 125- and 280-fold, respectively, in GTPase assays at human and guinea pig H2R-GsαS fusion proteins expressed in Sf9 insect cells. Docking studies on H2R models support the hypothesis that 2-aminothiazolyl and imidazolyl derivatives interact with H2Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H1, H3 and H4 Receptors. Moreover, unlike amthamine, the 4-methyl group does not significantly contribute to the H2R agonism of N(G)-acylated 2-amino-4-methylthiazol-5-ylpropylguanidines.
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synthesis and pharmacological characterization of novel fluorescent Histamine H2 Receptor ligands derived from aminopotentidine
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Sheng Xue Xie, Roland Seifert, Günther Bernhardt, Georgiana Petrache, Erich H Schneider, Armin BuschauerAbstract:In an effort to develop a non-radioactive alternative to the [3H]tiotidine and [125I]iodoaminopotentidine binding assays for the Histamine H2-Receptor (H2R), primary amines related to aminopotentidine were prepared and coupled with the succinimidyl esters of the bulky fluorescent dyes S0536 and BODIPY 650/665-X. The primary amines exhibited different degrees of antagonistic potency at the human and guinea pig H2R. Surprisingly, one compound (5) coupled to the cyanine dye S0536 acted as potent partial agonist/antagonist at the H2R (KB approximately 50 nM; EC50 approximately 100-150 nM). Compounds coupled to the BODIPY dye exhibited moderately high H2R-affinity, too. Thus, the H2R accommodates bulky fluorophores, probably through interaction with extracellular Receptor domains. The compounds presented herein provide a starting point for the optimization of fluorescent H2R ligands with respect to affinity and fluorescence as valuable tools to analyze the molecular mechanisms of H2R activation.
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structure activity relationships of Histamine H2 Receptor ligands
Mini-reviews in Medicinal Chemistry, 2004Co-Authors: Stefan Dove, Sigurd Elz, Roland Seifert, Armin BuschauerAbstract:Recent research on Histamine H2 Receptor agonists was focused on quantitative structure-activity relationships and Receptor models explaining the activity of imidazolylpropylguanidines. Their selectivity for guinea pig vs. human isoforms was investigated using H2 Receptor-Gsalpha fusion proteins and attributed to amino acid differences in transmembrane domains 1 and 7. New antagonists result from approaches to improve pharmacokinetic properties and to design hybrid drugs which additionally have gastroprotective or anti H. pylori activity.
Yasushi Fukushima - One of the best experts on this subject based on the ideXlab platform.
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disruption of Histamine H2 Receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis
Clinical Science, 2014Co-Authors: Zhi Zeng, Yasushi Fukushima, Liang Shen, Tao Luo, Xuan Wei, Jingwen Zhang, Shiping Cao, Xiaobo Huang, Jianping Bin, Masafumi KitakazeAbstract:Histamine H2 Receptor (H2R) blockade has been reported to be beneficial for patients with chronic heart failure (CHF), but the mechanisms involved are not entirely clear. In the present study, we assessed the influences of H2R disruption on left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis. H2R-knockout mice and their wild-type littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as in murine hearts. After 4 weeks, H2R-knockout mice had higher echocardiographic LV fractional shortening, a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, markedly lower pulmonary congestion compared with the wild-type mice. Similar results were obtained in wild-type TAC mice treated with H2R blocker famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R-knockout mice. H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that a lack of H2R generates resistance towards heart failure and the process is associated with the inhibition of cardiac fibrosis and apoptosis, adding to the rationale for using H2R blockers to treat patients with CHF.
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Histamine H2 Receptor activation exacerbates myocardial ischemia reperfusion injury by disturbing mitochondrial and endothelial function
Basic Research in Cardiology, 2013Co-Authors: Tao Luo, Yasushi Fukushima, Zhi Zeng, Jianping Bin, Masafumi Kitakaze, Baihe Chen, Zonglei Zhao, Meng Dai, Qiaobing Huang, Yulin LiaoAbstract:There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the Histamine H2 Receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum Histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum Histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, Histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.
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agonist induced internalization of Histamine H2 Receptor and activation of extracellular signal regulated kinases are dynamin dependent
Journal of Neurochemistry, 2008Co-Authors: Atsuo Kuramasu, Kay Maeda, Kazuki Kinoshita, Shiori Takayanagi, Yasushi Fukushima, Takehiko Watanabe, Teruyuki Yanagisawa, Jun Sukegawa, Kazuhiko YanaiAbstract:Histamine H2 Receptor (H2R) is a member of G protein-coupled Receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the Receptor, activation of extracellular signal-regulated kinases ERK1/2, and Receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type Receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself.
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structural and functional characterization of gastric mucosa and central nervous system in Histamine H2 Receptor null mice
European Journal of Pharmacology, 2003Co-Authors: Yasushi Fukushima, Takayuki Shindo, Motonobu Anai, Toshihito Saitoh, Yuhui Wang, Midori Fujishiro, Yoshio Ohashi, Takehide Ogihara, Kouichi Inukai, Hiraku OnoAbstract:Abstract To examine the physiological role of the Histamine H2 Receptor, Histamine H2 Receptor-null mice were generated by homologous recombination. Histamine H2 Receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in Histamine H2 Receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in Histamine H2 Receptor-null mice, gastric pH was elevated by both muscarinic M3 and gastrin antagonists. Thus, both gastrin and muscarinic Receptors appear to be directly involved in maintaining gastric pH in Histamine H2 Receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from Histamine H2 Receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from Histamine H2 Receptor-null mice. Therefore, it is possible that the abnormal gastric glands in Histamine H2 Receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the Histamine H2 Receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of Histamine H2 Receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin Receptors are functional in parietal cells in Histamine H2 Receptor-null mice, (2) abnormal gastric glands in Histamine H2 Receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) Histamine H2 Receptors are functional in the central nervous system.
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palmitoylation of the canine Histamine H2 Receptor occurs at cys 305 and is important for cell surface targeting
Biochimica et Biophysica Acta, 2001Co-Authors: Yasushi Fukushima, Motonobu Anai, Toshihito Saitoh, Takehide Ogihara, Kouichi Inukai, Hiraku Ono, Makoto Funaki, Hideyuki Sakoda, Yukiko Onishi, Midori FujishiroAbstract:To determine the presence and functional role of the Histamine H2 Receptor (H2R) palmitoylation, a Receptor with a Cys(305) to Ala (A(305) Receptor) mutation was generated. Wild-type (WT) and A(305) Receptors were tagged at their N-termini with a hemagglutinin (HA) epitope. WT, but not A(305), Receptors incorporated [3H]palmitate by metabolic labeling, indicating that the H2R is palmitoylated at Cys(305). Immunocytochemistry of WT and A(305) Receptors expressed in COS7 cells revealed WT Receptors to be distributed at the plasma membrane, while the majority of A(305) Receptors were localized intracellularly with only a small portion being at the plasma membrane. However, the affinity of the A(305) Receptor for tiotidine was comparable to that of the WT Receptor. In addition, when the amounts of cell surface Receptors as determined by anti-HA antibody binding were equivalent, A(305) Receptors mediated production of more cAMP than WT Receptors. Preincubation of COS7 cells expressing each Receptor with 10(-5) M Histamine for 30 min reduced subsequent cAMP production in response to Histamine via the Receptors to similar extents, indicating that palmitoylation is not necessary for desensitization. In addition, cell surface A(305) Receptors were capable of being internalized from the cell surface at a rate and extent similar to those of WT Receptors. Finally, CHO cell lines stably expressing either WT or A(305) Receptors were incubated with 10(-5) M Histamine for 1, 6, 12 and 24 h. Total amounts of WT and A(305) Receptors, as determined by tiotidine binding, were reduced by incubation, indicating downregulation. Downregulation of the A(305) Receptor was more extensive than that of the WT Receptor. Thus, palmitoylation of the H2R might be important for targeting to the cell surface and stability.
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dimeric carbamoylguanidine type Histamine H2 Receptor ligands a new class of potent and selective agonists
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Nicole Kagermeier, Roland Seifert, Günther Bernhardt, Paul Baumeister, Kristin Werner, Max Keller, Armin BuschauerAbstract:The bioisosteric replacement of the acylguanidine moieties in dimeric Histamine H2 Receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of Histamine when studied in [35S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over Histamine Receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes.
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3h ur de257 development of a tritium labeled squaramide type selective Histamine H2 Receptor antagonist
ChemMedChem, 2015Co-Authors: Paul Baumeister, Sigurd Elz, Günther Bernhardt, Daniela Erdmann, Sabrina Biselli, Nicole Kagermeier, Armin BuschauerAbstract:A series of new piperidinomethylphenoxypropylamine-type Histamine H2 Receptor (H2R) antagonists with different substituted “urea equivalents” was synthesized and characterized in functional in vitro assays. N-6-(3,4-Dioxo-2-{3-3-(piperidin-1-ylmethyl)phenoxy]-propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide (3HUR-DE257, 24b) was selected for radiosynthesis. The radioligand (specific activity: 63 Ci • mmol-1) had a high affinity for the human, the rat and the guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 (24a) revealed high H2R selectivity on membranes of Sf9 cells, expressing the respective hHxR subtype (Ki values: hH1R: >10000 nM, hH2R: 28 nM, hH3R: 3800 nM, hH4R: >10000 nM). Regardless of insurmountable antagonism, characteristic for this class of compounds depending on the type of functional assay, and of rebinding of 24b to the H2R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2R affinities in competition binding assays.
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the bivalent ligand approach leads to highly potent and selective acylguanidine type Histamine H2 Receptor agonists
Journal of Medicinal Chemistry, 2012Co-Authors: Tobias Birnkammer, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt, Nicole Kagermeier, Anja Spickenreither, Irena Brunskole, Miroslaw Lopuch, Armin BuschauerAbstract:Bivalent Histamine H2 Receptor (H2R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by NG-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H2R agonism in GTPase and [35S]GTPγS binding assays at guinea pig (gp) and human (h) H2R-GsαS fusion proteins including various H2R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H1, H3, and H4 Receptors. The bivalent ligands are H2R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than Histamine at the gpH2R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H2R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH2 groups) to simultaneously occupy two orth...
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NG‐Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H2 Receptor Agonists
ChemMedChem, 2009Co-Authors: Anja Kraus, Prasanta Ghorai, Tobias Birnkammer, David Schnell, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt, Armin BuschauerAbstract:The bioisosteric replacement of the guanidino group in arpromidine-like Histamine H2 Receptor (H2R) agonists by an acylguanidine moiety is a useful approach to obtain potent H2R agonists with improved oral bioavailability and penetration across the blood brain barrier. Unfortunately, the selectivity of such N(G)-acylated imidazolylpropyl-guanidines for the H2R is poor, in particular versus Histamine H3 (H3R) and H4 Receptors (H4R). This drawback appears to depend on the "privileged" imidazolylpropylguanidine structure. The 2-amino-4-methylthiazol-5-yl moiety is a bioisostere of the imidazole ring in the moderately potent H2R selective Histamine analogue amthamine. This approach was successfully applied to acylguanidine-type H2R agonists. The aminothiazoles are nearly equipotent with the corresponding imidazoles as H2R agonists. Compared to Histamine, the potency is increased up to 40-fold on the guinea pig right atrium and up to 125- and 280-fold, respectively, in GTPase assays at human and guinea pig H2R-GsαS fusion proteins expressed in Sf9 insect cells. Docking studies on H2R models support the hypothesis that 2-aminothiazolyl and imidazolyl derivatives interact with H2Rs as bioisosteres. In contrast to the imidazoles, the aminothiazoles are devoid of agonistic or relevant antagonistic effects on H1, H3 and H4 Receptors. Moreover, unlike amthamine, the 4-methyl group does not significantly contribute to the H2R agonism of N(G)-acylated 2-amino-4-methylthiazol-5-ylpropylguanidines.
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acylguanidines as bioisosteres of guanidines ng acylated imidazolylpropylguanidines a new class of Histamine H2 Receptor agonists
Journal of Medicinal Chemistry, 2008Co-Authors: Prasanta Ghorai, Anja Kraus, David Schnell, Stefan Dove, Günther Bernhardt, Erich H Schneider, Max Keller, Carsten Gotte, Patrick Igel, Manfred ZabelAbstract:N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent Histamine H2-Receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4−5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant Receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to ...