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Differently fluorescence-labelled dibenzodiazepinone-type muscarinic acetylcholine receptor ligands with high M₂R affinity.

ABSTRACT: A series of fluorescent dibenzodiazepinone-type muscarinic acetylcholine M₂ receptor (M₂R) ligands was synthesized using various fluorescent dyes (5-TAMRA, λ _ex/λ _em ≈ 547/576 nm; BODIPY 630/650, λ _ex/λ _em ≈ 625/640 nm; pyridinium dye Py-1, λ _ex/λ _em ≈ 611/665 nm and pyridinium dye Py-5, λ _ex/λ _em ≈ 465/732 nm). All fluorescent probes exhibited high M₂R affinity (pK _i (radioligand competition binding): 8.75-9.62, pK _d (flow cytometry): 8.36-9.19), a very low preference for the M₂R over the M₁ and M₄ receptors and moderate to pronounced M₂R selectivity compared to the M₃ and M₅ receptors. The presented fluorescent ligands are considered useful molecular tools for future studies using methods such as fluorescence anisotropy and BRET based MR binding assays.

SUBMITTER: Gruber CG

PROVIDER: S-EPMC7650007 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Differently fluorescence-labelled dibenzodiazepinone-type muscarinic acetylcholine receptor ligands with high M2R affinity.

Gruber Corinna G CG Pegoli Andrea A Müller Christoph C Grätz Lukas L She Xueke X Keller Max M

RSC medicinal chemistry 20200608 7

A series of fluorescent dibenzodiazepinone-type muscarinic acetylcholine M2 receptor (M2R) ligands was synthesized using various fluorescent dyes (5-TAMRA, λ ex/λ em ≈ 547/576 nm; BODIPY 630/650, λ ex/λ em ≈ 625/640 nm; pyridinium dye Py-1, λ ex/λ em ≈ 611/665 nm and pyridinium dye Py-5, λ ex/λ em ≈ 465/732 nm). All fluorescent prob ...[more]

PMID: 33479678

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Project description:Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor control deficits, which is associated with the loss of striatal dopaminergic neurons from the substantia nigra. In parallel to dopaminergic denervation, there is an increase of acetylcholine within the striatum, resulting in a striatal dopaminergic-cholinergic neurotransmission imbalance. Currently, available PD pharmacotherapy (e.g., prodopaminergic drugs) does not reinstate the altered dopaminergic-cholinergic balance. In addition, it can eventually elicit cholinergic-related adverse effects. Here, we investigated the interplay between dopaminergic and cholinergic systems by assessing the physical and functional interaction of dopamine D2 and muscarinic acetylcholine M1 receptors (D2R and M1R, respectively), both expressed at striatopallidal medium spiny neurons. First, we provided evidence for the existence of D2R-M1R complexes via biochemical (i.e., co-immunoprecipitation) and biophysical (i.e., BRET1 and NanoBiT®) assays, performed in transiently transfected HEK293T cells. Subsequently, a D2R-M1R co-distribution in the mouse striatum was observed through double-immunofluorescence staining and AlphaLISA® immunoassay. Finally, we evaluated the functional interplay between both receptors via behavioral studies, by implementing the classical acute reserpine pharmacological animal model of experimental parkinsonism. Reserpinized mice were administered with a D2R-selective agonist (sumanirole) and/or an M1R-selective antagonist (VU0255035), and alterations in PD-related behavioral tasks (i.e., locomotor activity) were evaluated. Importantly, VU0255035 (10 mg/kg) potentiated the antiparkinsonian-like effects (i.e., increased locomotor activity and decreased catalepsy) of an ineffective sumanirole dose (3 mg/kg). Altogether, our data suggest the existence of putative striatal D2R/M1R heteromers, which might be a relevant target to manage PD motor impairments with fewer adverse effects.

Dataset Information

Differently fluorescence-labelled dibenzodiazepinone-type muscarinic acetylcholine receptor ligands with high M₂R affinity.

Publications

Differently fluorescence-labelled dibenzodiazepinone-type muscarinic acetylcholine receptor ligands with high M<sub>2</sub>R affinity.

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