Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R

Biselli, Sabrina; Bresinsky, Merlin; Tropmann, Katharina; Forster, Lisa; Honisch, Claudia; Buschauer, Armin; Bernhardt, Günther; Pockes, Steffen

doi:10.1016/j.ejmech.2021.113190

Cited by 10 publications

(23 citation statements)

References 49 publications

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“…The mini-G protein recruitment assay was performed as previously described using HEK293T cells stably expressing NlucN-mGs/hH 2 R-NlucC or NlucN-mGs/gpH 2 R-NlucC and UR-Po563 in various concentrations (Höring et al, 2020;Tropmann et al, 2021).…”

Section: Mini-g Protein Recruitment Assaymentioning

confidence: 99%

“…UR-Po563 (Biselli et al, 2021), UR-MB-158 and UR-MB-159 (Tropmann et al, 2021) were synthesized as dihydrochloride salts according to the literature (Fig. 1).…”

Section: Drugs and Materialsmentioning

confidence: 99%

“…As these effects have only been shown with dual-acting acetylcholinesterase inhibitors and H 3 R antagonists initiating this process by inhibiting presynaptic H 3 -autoreceptors (Darras et al, 2014;Khan et al, 2016;Sadek et al, 2016) the use of central nervous system-penetrating H 2 R agonists is of great interest. In the present work we wanted to test whether the recently published H 2 R agonists UR-Po563 (Biselli et al, 2021), UR-MB-158 and UR- MB-159 (Tropmann et al, 2021) (Fig. 1) act on the human cardiac H 2 R.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Gergs

Büxel

Bresinsky

et al. 2021

J Pharmacol Exp Ther

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In an integrative approach, we studied cardiac effects of recently published novel H 2 receptor agonists in the heart of mice that overexpress the human H 2 receptor (H 2 -TG), littermate wild type control mice (WT) and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H 2 receptor agonists UR-Po563, UR-MB-158 and UR-MB-159 increased force of contraction in left atrium from H 2 -TG with pEC 50 values of 8.27, 9.38, and 8.28, respectively, but not in WT. Likewise, UR-Po563, UR-MB-158 and UR-MB-159increased the beating rate in right atrium from H 2 -TG with pEC 50 values of 9.01, 9.24, and 7.91, respectively, but not in WT. These effects could be antagonized by famotidine, a H 2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff perfused hearts from H 2 -TG but not WT. Similarly, UR-Po563, UR-MB-158 or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H 2 -TG. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H 2 -TG were accompanied by an increase in the phosphorylation state of phospholamban. In summary, we report here three recently developed agonists functionally stimulating human cardiac H 2 receptors in vitro and in vivo.We speculate that these compounds might be of some merit to treat neurological disorders if their cardiac effects are blocked by concomitantly applied receptor antagonists that cannot pass through the blood-brain barrier or might be useful to treat congestive heart failure in patients.

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Section: Mini-g Protein Recruitment Assaymentioning

confidence: 99%

“…UR-Po563 (Biselli et al, 2021), UR-MB-158 and UR-MB-159 (Tropmann et al, 2021) were synthesized as dihydrochloride salts according to the literature (Fig. 1).…”

Section: Drugs and Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Gergs

Büxel

Bresinsky

et al. 2021

J Pharmacol Exp Ther

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“…Although a lot of progress was made in the field of H 2 R radioligands, some challenges remain. For example, a recently published study suggests that ligands with similar structural features as [ 3 H]UR-KAT479 possess a high affinity for dopamine receptors of the D 2 -like family, specifically for the dopamine D 3 receptor [18]. This drawback might hamper a possible application in autoradiography experiments.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

“…In contrast, H 2 receptor agonists have not yet found their way into the world's drug portfolio. Although a large number of highly potent and subtypeselective agonists has already been published, these ligands are predominantly applied in basic research studies within academia [11][12][13][14][15][16][17][18]. However, the aforementioned properties turn them into valuable pharmacological tools that could be of great importance to elucidate the largely unknown role of the H 2 R in the central nervous system (CNS) [3,15].…”

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confidence: 99%

Histamine H ₂ Receptor Radioligands: Triumphs and Challenges

Pockes

Tropmann

2021

Future Med. Chem.

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Since the discovery of the histamine H2 receptor (H2R), radioligands were among the most powerful tools to investigate its role and function. Initially, radiolabeling was used to investigate human and rodent tissues regarding their receptor expression. Later, radioligands gained increasing significance as pharmacological tools in in vitro assays. Although tritium-labeling was mainly used for this purpose, labeling with carbon-14 is preferred for metabolic studies of drug candidates. After the more-or-less successful application of numerous labeled H2R antagonists, the recent development of the G protein-biased radioligand [3H]UR-KAT479 represents another step forward to elucidate the widely unknown role of the H2R in the central nervous system through future studies.

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Commercial Transaminases for the Asymmetric Synthesis of Bulky Amines

Haarr,

Sriwong,

O'Reilly

2024

Eur J Org Chem

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Transaminase‐catalysed asymmetric amination is a valuable transformation for the synthesis of chiral amines. However, its use in synthetic chemistry has been curtailed by a narrow substrate scope and limited information on commercially available catalysts. In this work we have explored the substrate scope of selected commercially available transaminases, focusing on prochiral ketones bearing two bulky substituents and their application in both enzyme‐catalysed and enzyme‐triggered reactions. (R)‐ and/or (S)‐selective enzymes converted methyl‐, isopropyl‐, n‐butyl‐, and cyclohexyl‐phenone substrates to the corresponding amines in the range of 6 ‐ >99% ee. In some cases, a stereochemical switch was detected, in which (R)‐enantioselectivity was observed with enzymes typically assigned as (S)‐selective. Upscaling of selected biotransformations provided chiral amines, in >99% ee and up to 40% isolated yield. Furthermore, transaminase‐triggered reactions, which were previously limited to methyl‐ and ethyl‐derivatives, were expanded to phenyl‐derivatives for the formation of a cis‐2,6‐disubstituted piperidine and 2,4‐diphenyl pyrroline, and isolated in up to 67% yield.

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Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R

Cited by 10 publications

References 49 publications

Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Histamine H ₂ Receptor Radioligands: Triumphs and Challenges

Commercial Transaminases for the Asymmetric Synthesis of Bulky Amines

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Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R

Cited by 10 publications

References 49 publications

Cardiac Effects of Novel Histamine H2 Receptor Agonists

Cardiac Effects of Novel Histamine H2 Receptor Agonists

Histamine H 2 Receptor Radioligands: Triumphs and Challenges

Commercial Transaminases for the Asymmetric Synthesis of Bulky Amines

Contact Info

Product

Resources

About

Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Histamine H ₂ Receptor Radioligands: Triumphs and Challenges