Flavonoids with M1 muscarinic acetylcholine receptor binding activity - PubMed (original) (raw)

Flavonoids with M1 muscarinic acetylcholine receptor binding activity

Meyyammai Swaminathan et al. Molecules. 2014.

Abstract

Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer's disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (Ki=40-110 µM), comparable to that of acetylcholine (Ki=59 µM). Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

General structure of the investigated flavones and flavonols.

Scheme 1

Scheme 1

Synthesis of flavones 1–4.

Scheme 2

Scheme 2

Synthesis of flavonols 9–10.

Figure 2

Figure 2

Displacement curves for the binding of [3H]N-methylscopolamine to the M1 mAChR in the presence of (A) 3',4',5',5,6,7-hexamethoxyflavone (4), luteolin (6) and ombuin (9) and (B) acetylcholine (ACh) and pilocarpine. Receptor membranes (13 µg protein/well) were incubated with N-methylscopolamine (0.2 nM) in the presence of the compounds at 27 °C for 120 min. Each data point is expressed as a mean ± SEM (n = 2).

Figure 3

Figure 3

3D representations of the docking poses of (A) ombuin (9) (brown) and (B) quercetin (12) (blue-green) in complex with the human M1 mAChR model obtained from induced-fit docking using Glide v5.7 and Prime v3.0 (Schrödinger LLC) with side views and top views (from the extracellular surface) depicted in the left hand and right hand panels, respectively. For the purpose of clarity, only D105 and W378 from among the active site residues are depicted in stick representation and some of the transmembrane helices are not shown.

Figure 4

Figure 4

2D representations of the ligand-receptor interactions of (A) ombuin (9) and (B) quercetin (12) in complex with the human M1 mAChR model obtained from induced-fit docking using Glide v5.7 and Prime v3.0 (Schrödinger LLC), showing pi-pi stacking interactions (green lines), hydrogen bonds involving backbone atoms (solid purple arrows) and hydrogen bonds involving side-chain atoms (dashed purple arrows). Negatively-charged, polar and hydrophobic residues are depicted with red, light blue and green circles, respectively.

Figure 5

Figure 5

The structural binding analysis map for acetylcholine and a composite map for the active flavonoids, 3',4',5',5,6,7-hexamethoxyflavone (4), luteolin (6) and ombuin (9), obtained from molecular modelling studies. Negatively-charged, polar and hydrophobic residues are depicted in red, blue and dark green, respectively.

Figure 6

Figure 6

3D representations of the docking poses of (A) ombuin-3'-glucuronide and (B) ombuin-3'-sulfate in complex with the human M1 mAChR model obtained from induced-fit docking using Glide v5.7 and Prime v3.0 (Schrödinger LLC) with side views and top views (from the extracellular surface) depicted in the left hand and right hand panels, respectively. For the purpose of clarity, only D105 and W378 from among the active site residues are depicted in stick representation and some of the transmembrane helices are not shown. The carbon atoms of the glucuronide moiety in ombuin-3'-glucuronide are coloured in light green.

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