Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness

Wingen, Kerstin; Schwed, J. Stephan; Isensee, Kathleen; Weizel, Lilia; Živković, Aleksandra; Odazic, Dalibor; Stark, Holger

doi:10.1016/j.bmcl.2014.03.098

Cited by 11 publications

(17 citation statements)

References 32 publications

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“…32,33 A selective "Staudinger"-type reduction of a single azide group in a biphasic water/ethyl acetate mixture afforded the final linker 9 with 77% yield. 34 Subsequently, 5 was coupled with 9 using EDC/HOBt as coupling reagents under microwave irradiation to afford product 10, 26 which was reduced to the primary amine 11 by a "Staudinger" reaction (Scheme 2). In the final step, 11 was coupled with the 5-TAMRA NHS ester in DMF to afford fluorescent ligand UR-NR266 (12, Scheme 2).…”

Section: ■ Introductionsupporting

confidence: 90%

“…Structure activity relationships showed a high tolerance of the ligand toward structural changes at the para position of the benzylic piperidine moiety. 26 Thus, this position of the molecule has been chosen to attach the linker via an amide group.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Acid catalyzed hydrolysis of 4 afforded the free acid 5 as a dihydrochloride. 26 The synthesis of the linker (Scheme 1B), which is necessary for the connection of the pharmacophore with the fluorophore, started from the commercially available tetraethylene glycol 6. In the first step, mesylate groups were introduced (7) as good leaving groups, followed by subsequent treatment with sodium azide to afford 8.…”

Section: ■ Introductionmentioning

confidence: 99%

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A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H₃ Receptor

et al. 2021

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The histamine H 3 receptor (H 3 R) is considered an attractive drug target for various neurological diseases. We here report the synthesis of UR-NR266, a novel fluorescent H 3 R ligand. Broad pharmacological characterization revealed UR-NR266 as a sub-nanomolar compound at the H 3 R with an exceptional selectivity profile within the histamine receptor family. The presented neutral antagonist showed fast association to its target and complete dissociation in kinetic binding studies. Detailed characterization of standard H 3 R ligands in NanoBRET competition binding using UR-NR266 highlights its value as a versatile pharmacological tool to analyze future H 3 R ligands. The low nonspecific binding observed in all experiments could also be verified in TIRF and confocal microscopy. This fluorescent probe allows the highly specific analysis of native H 3 R in various assays ranging from optical high throughput technologies to biophysical analyses and single-molecule studies in its natural environment. An off-target screening at 14 receptors revealed UR-NR266 as a selective compound.

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Section: ■ Introductionsupporting

confidence: 90%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H₃ Receptor

et al. 2021

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“…The investigated compounds Andrographolide and Asunaprevir were drawn using Marvin sketch [ 26 ]. Ligand optimization was carried out using Chemistry at Harvard Molecular Mechanics (CHARMm) and macro molecular force field (MMF) followed by energy minimization protocol [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants UsingIn SilicoApproaches

Chandramohan¹,

Kaphle²,

Chekuri³

et al. 2015

Advances in Virology

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Current combination therapy of PEG-INF and ribavirin against the Hepatitis C Virus (HCV) genotype-1 infections is ineffective in maintaining sustained viral response in 50% of the infection cases. New compounds in the form of protease inhibitors can complement the combination therapy. Asunaprevir is new to the drug regiment as the NS3-4A protease inhibitor, but it is susceptible to two mutations, namely, R155K and D168A in the protein. Thus, in our study, we sought to evaluate Andrographolide, a labdane-diterpenoid from the Andrographis paniculata plant as an effective compound for inhibiting the NS3-4A protease as well as its concomitant drug-resistant mutants by using molecular docking and dynamic simulations. Our study shows that Andrographolide has best docking scores of −15.0862, −15.2322, and −13.9072 compared to those of Asunaprevir −3.7159, −2.6431, and −5.4149 with wild-type R155K and D168A mutants, respectively. Also, as shown in the MD simulations, the compound was good in binding the target proteins and maintains strong bonds causing very less to negligible perturbation in the protein backbone structures. Our results validate the susceptibility of Asunaprevir to protein variants as seen from our docking studies and trajectory period analysis. Therefore, from our study, we hope to add one more option in the drug regiment to tackle drug resistance in HCV infections.

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“…The main compounds presenting antagonist activity in H 3 R are thioperamide, ciproxifan, clobenpropit, and proxifan (Figure ), which keep the imidazole moiety from histamine . As the imidazole ring is associated to CYP450 inhibition, newer non‐imidazole compounds have been designed to circumvent this undesirable effect . A review covering the H 3 R ligands was recently published .…”

Section: Histamine and Histamine Receptor Ligandsmentioning

confidence: 99%

Histamine H₄ Receptor Ligands: Future Applications and State of Art

Corrêa

Fernandes

2014

Chem Biol Drug Des

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Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.

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Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness

Cited by 11 publications

References 32 publications

A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H₃ Receptor

A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H₃ Receptor

Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants UsingIn SilicoApproaches

Histamine H₄ Receptor Ligands: Future Applications and State of Art

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Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness

Cited by 11 publications

References 32 publications

A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H3 Receptor

A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H3 Receptor

Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants UsingIn SilicoApproaches

Histamine H4 Receptor Ligands: Future Applications and State of Art

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A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H₃ Receptor

A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H₃ Receptor

Histamine H₄ Receptor Ligands: Future Applications and State of Art