Design and synthesis of a fluorescent muscarinic antagonist

Jones, Lyn H.; Randall, A. W.; Napier, Carolyn; Trevethick, Michael A.; Sreckovic, Sasha; Watson, Jessica

doi:10.1016/j.bmcl.2007.11.022

Cited by 16 publications

(15 citation statements)

References 4 publications

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“…30,31 Likewise, conjugation of the MR ligands tolterodine, telenzepine and AC-42 to fluorescent dyes resulted in probes with high to moderate M 1 R affinity (compounds 2-4, Figure 1A). [32][33][34][35] Compounds 1 and 4 were reported to bind bitopically/dualsterically to the hM 1 R, 30,35 i.e. they bind simultaneously to the orthosteric and an allosteric site of the receptor.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to the M 1 R, reports on fluorescent probes for the M 2 -M 5 receptor subtypes, characterized at cloned MRs, are rare: the non-selective fluorescent M 1 R ligands 2 and 3 were reported to exhibit also high M 2 -M 5 receptor and high M 2 R affinity, respectively (Figure 1A), 33,36 and pyridinium-styryl-type fluorescent dyes were shown to bind to all MR subtypes at medium nanomolar concentrations. 37 30,[32][33][34][35][36] (in case of 1 30 and 2, 33 . 38,39 Prompted by the recently reported synthesis and characterization of radiolabeled dualsteric M 2 R antagonists derived from the M 2 R preferring dibenzodiazepinone DIBA (5) 40 (for instance,…”

Section: Introductionmentioning

confidence: 99%

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Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

et al. 2020

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Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M R affinities (pK i (radioligand competition binding): 9.10-9.59). Binding studies at M 1 and M 3 -M 5 receptors indicated a M 2 R preference. Flow cytometric and high-content imaging saturation and competition binding (M 1 R, M 2 R and M 4 R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM 2 R cells). Results from dissociation and saturation binding experiments (M 2 R) in the presence of allosteric M 2 R modulators (dissociation: W84, LY2119620 and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M 2 R in imaging and binding studies, and suggest that they have a dualsteric mode of action.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

et al. 2020

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“…The novel fluorescent ligand showed only a three‐fold loss in affinity compared to the parent ligand. However, it lacked selectivity towards M 3 R [108] …”

Section: Fluorescent Ligands For Gpcrsmentioning

confidence: 99%

Lighting Up the Plasma Membrane: Development and Applications of Fluorescent Ligands for Transmembrane Proteins

Borgarelli

Klingl

Escamilla-Ayala

et al. 2021

Chemistry A European J

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Despite the fact that transmembrane proteins represent the main therapeutic targets for decades, complete and in‐depth knowledge about their biochemical and pharmacological profiling is not fully available. In this regard, target‐tailored small‐molecule fluorescent ligands are a viable approach to fill in the missing pieces of the puzzle. Such tools, coupled with the ability of high‐precision optical techniques to image with an unprecedented resolution at a single‐molecule level, helped unraveling many of the conundrums related to plasma proteins’ life‐cycle and druggability. Herein, we review the recent progress made during the last two decades in fluorescent ligand design and potential applications in fluorescence microscopy of voltage‐gated ion channels, ligand‐gated ion channels and G‐coupled protein receptors.

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“…A fluorescent antagonist ( 22 ) of the muscarinic M 3 receptor (M 3 R) has been reported by Jones et al . (), by linking the non‐subtype selective M 3 R antagonist tolterodine to the commercially available fluorophore BODIPY 630/650‐NHS ester. Conjugate 22 displayed a threefold loss in affinity for the human M 3 R compared with tolterodine, and also approximately the same fold‐loss in affinity across the other human muscarinic receptor subtypes.…”

Section: Fluorescent Ligands For Gpcrsmentioning

confidence: 99%

The evolving small‐molecule fluorescent‐conjugate toolbox for Class A GPCRs

Vernall

Hill

Kellam

2014

British J Pharmacology

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The past decade has witnessed fluorescently tagged drug molecules gaining significant attraction in their use as pharmacological tools with which to visualize and interrogate receptor targets at the single-cell level. Additionally, one can generate detailed pharmacological information, such as affinity measurements, down to almost single-molecule detection limits. The now accepted utilization of fluorescence-based readouts in high-throughput/high-content screening provides further evidence that fluorescent molecules offer a safer and more adaptable substitute to radioligands in molecular pharmacology and drug discovery. One such drug-target family that has received considerable attention are the GPCRs; this review therefore summarizes the most recent developments in the area of fluorescent ligand design for this important drug target. We assess recently reported fluorescent conjugates by adopting a receptor-family-based approach, highlighting some of the strengths and weaknesses of the individual molecules and their subsequent use. This review adds further strength to the arguments that fluorescent ligand design and synthesis requires careful planning and execution; providing examples illustrating that selection of the correct fluorescent dye, linker length/composition and geographic attachment point to the drug scaffold can all influence the ultimate selectivity and potency of the final conjugate when compared with its unlabelled precursor. When optimized appropriately, the resultant fluorescent conjugates have been successfully employed in an array of assay formats, including flow cytometry, fluorescence microscopy, FRET and scanning confocal microscopy. It is clear that fluorescently labelled GPCR ligands remain a developing and dynamic research arena. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx

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Design and synthesis of a fluorescent muscarinic antagonist

Cited by 16 publications

References 4 publications

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

Lighting Up the Plasma Membrane: Development and Applications of Fluorescent Ligands for Transmembrane Proteins

The evolving small‐molecule fluorescent‐conjugate toolbox for Class A GPCRs

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Design and synthesis of a fluorescent muscarinic antagonist

Cited by 16 publications

References 4 publications

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor

Lighting Up the Plasma Membrane: Development and Applications of Fluorescent Ligands for Transmembrane Proteins

The evolving small‐molecule fluorescent‐conjugate toolbox for Class A GPCRs

Contact Info

Product

Resources

About

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M₂ Receptor