140872-99-7Relevant academic research and scientific papers
Anti-Helicobacter pylori agents endowed with H2-antagonist properties
Sorba, Giovanni,Bertinaria, Massimo,Di Stilo, Antonella,Gasco, Alberto,Scaltrito, Maria M.,Brenciaglia, Maria I.,Dubini, Francesco
, p. 403 - 406 (2001)
New anti-Helicobacter pylori (H. pylori) agents endowed with H2-antagonists properties were obtained by combining the lamtidine derived pharmacophoric group with the antibiotic calvatic acid. All the compounds were tested for their irreversible H2-antagonist properties and for their ability to inhibit 20 H. pylori strains, two of them metronidazole resistant. The most active derivative (compound 4) displayed antimicrobial activity similar to metronidazole.
An integrated approach toward nanobret tracers for analysis of gpcr ligand engagement
Boursier, Michelle E.,Hall, Mary P.,Hurst, Robin,Killoran, Michael P.,Kirkland, Thomas A.,Levin, Sergiy,Machleidt, Thomas,Ohana, Rachel Friedman,Zimmerman, Kristopher
, (2021/05/31)
Gaining insight into the pharmacology of ligand engagement with G-protein coupled receptors (GPCRs) under biologically relevant conditions is vital to both drug discovery and basic research. NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a robust and sensitive method to quantify ligand engagement with specific GPCRs genetically fused to NanoLuc luciferase or the luminogenic HiBiT peptide. However, development of fluorescent tracers is often challenging and remains the principal bottleneck for this approach. One way to alleviate the burden of developing a specific tracer for each receptor is using promiscuous tracers, which is made possible by the intrinsic specificity of BRET. Here, we devised an integrated tracer discovery workflow that couples machine learning-guided in silico screening for scaffolds displaying promiscuous binding to GPCRs with a blend of synthetic strategies to rapidly generate multiple tracer candidates. Subsequently, these candidates were evaluated for binding in a NanoBRET ligand-engagement screen across a library of HiBiT-tagged GPCRs. Employing this workflow, we generated several promiscuous fluorescent tracers that can effectively engage multiple GPCRs, demonstrating the efficiency of this approach. We believe that this workflow has the potential to accelerate discovery of NanoBRET fluorescent tracers for GPCRs and other target classes.
[3H]UR-DE257: Development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist
Baumeister, Paul,Erdmann, Daniela,Biselli, Sabrina,Kagermeier, Nicole,Elz, Sigurd,Bernhardt, Günther,Buschauer, Armin
, p. 83 - 93 (2015/06/01)
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. Based on these data as selection criteria, radiosynthesis of N-[6-(3,4-dioxo-2-{3-[3-(piperidin-1-ylmethyl)phenoxy]propylamino}cyclobut-1-enylamino)hexyl]-(2,3-3H2)propionic amide ([3H]UR-DE257) was performed. The radioligand (specific activity: 63Cimmol-1) had high affinity for human, rat, and guinea pig H2R (hH2R, Sf9 cells: Kd, saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 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). In spite of insurmountable antagonism, probably due to rebinding of [3H]URDE257 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.
Synthesis and pharmacological characterization of novel fluorescent histamine H2-receptor ligands derived from aminopotentidine
Xie, Sheng-Xue,Petrache, Georgiana,Schneider, Erich,Ye, Qi-Zhuang,Bernhardt, Guenther,Seifert, Roland,Buschauer, Armin
, p. 3886 - 3890 (2008/09/21)
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 ～ 50 nM; EC50 ～ 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.
Synthesis and pharmacological activity of fluorescent histamine H2 receptor antagonists related to potentidine
Li, Liantao,Kracht, Julia,Peng, Shiqi,Bernhardt, Guenther,Elz, Sigurd,Buschauer, Armin
, p. 1717 - 1720 (2007/10/03)
Fluorescently labeled histamine H2 receptor antagonists were synthesized starting from N-cyano-N′-[3-(3-piperidin-1-ylmethylphenoxy)propyl]guanidines with an additional N″-ω-aminoalkyl substituent (chain lengths 2-8 methylene groups) or from 3-(3-piperidin-1-ylmethylphenoxy)propylamine. The primary amino group was derivatized with various fluorophores (fluorescein, acridine, dansyl, nitrobenzoxadiazole (NBD), indolo[2,3-a]quinolizine). On the isolated spontaneously beating guinea pig right atrium most of the fluorescent probes were only weakly active, however, the NBD-labeled substances proved to be potent histamine H2 receptor antagonists achieving pA2 values in the range of 7.5-8.0, comparable to the activity of famotidine.
Synthesis and pharmacological characterization of new H2-antagonists containing NO-donor moieties, endowed with mixed antisecretory and gastroprotective activities
Bertinaria, Massimo,Sorba, Giovanni,Medana, Claudio,Cena, Clara,Adami, Maristella,Morini, Giuseppina,Pozzoli, Cristina,Coruzzi, Gabriella,Gasco, Alberto
, p. 287 - 299 (2007/10/03)
Synthesis, structural characterization, and pharmacological profile of a series of H2-antagonists able to release nitric oxide (NO) are reported. These compounds were obtained by using appropriate spacers to join H2- antagonistic pharmacophoric groups related to lamtidine and tiotidine to different NO-donor moieties such as esters of HNO3, nitrosothio groups, and benzenesulfonyl-substituted furoxans. All of the compounds were tested for their NO-donor properties. Furthermore, the hybrid structures synthesized, together with some selected reference compounds, were tested for their H2- antagonistic properties, both in vitro and in vivo, and for their gastroprotective effects. Only the hybrid compounds were able both to antagonize histamine effects on guinea-pig papillary muscle and to display in vivo antisecretory and gastroprotective action. The best results were obtained with the lamtidine/furoxan hybrid structure.
Iodoaminopotentidine and related compounds: A new class of ligands with high affinity and selectivity for the histamine H2 receptor
Hirschfeld,Buschauer,Elz,Schunack,Ruat,Traiffort,Schwartz
, p. 2231 - 2238 (2007/10/02)
The synthesis and biological evaluation of a new class of histamine H2 antagonists with N-cyano-N'-[ω-[3-(1- piperidinylmethyl)phenoxy]alkyl]guanidine partial structure are described as part of an extensive research program to find model compounds for the development of new radioligands with high H2 affinity and specific activity. High receptor affinity is achieved by an additional (substituted) aromatic ring, which is connected with the third guanidine N by a carbon chain spacer and an amine, carboxamide, ester, or sulfonamide link ('polar group'). In functional studies for H2 antagonistic activity and other pharmacological actions [e.g. H1 antihistaminic, antimuscarinic, antiadrenergic (α1, β1), 5-HT2 blocking activity] in the isolated guinea pig atrium and ileum and rat aorta and tail artery, the compounds proved to be highly potent and selective histamine H2 receptor antagonists. The H2 antagonistic activity is mainly depending on the length of both the N'-alkyl chain (chain A) and the N''-spacer (chain B). Compounds with a C3 chain A and a C2 chain B are most potent in the preferred group of substances, i.e., the carboxamide series. A wide variety of substituents at the aromatic ring is tolerated, among them iodine, amino, and azido groups. These compounds are up to 32 times more potent than cimetidine in the isolated guinea pig right atrium. The replacement of the carboxamide by an ester group (44c) is well tolerated, while replacement of the cyanoguanidine by an urea group results in nearly 100-fold decrease in activity (46c,e). The iodinated benzamides are among the most potent H2 antagonists known so far. The [125I]-labeled form of 31f ([125]iodoaminopotendine, [125I]-N-[2-(4-amino-3-iodobenzamido)ethyl]- N'-cyano-N''-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine) and its photolabile analogue 31h ([125I]iodoazidopotentidine, [125I]-N-[2-(4- azido-3-iodobenzamido)ethyl]-N'-cyano-N''-[3-[3-(1-piperidinyl- methyl)phenoxy]propyl]guanidine) proved to be useful probes for reversible and irreversible labeling of the histamine H2 receptor. Radioligand binding studies in guinea pig cerebral membranes revealed considerably higher H2 receptor affinity for 31f (pK(i) = 9.15), 31h (pK(i) = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H2 receptors in membranes.
