Fluorescent Pirenzepine Derivatives as Potential Bitopic Ligands of the Human M1 Muscarinic Receptor

Tahtaoui, Chouaib; Parrot, Isabelle; Klotz, Philippe; Guillier, Fabrice; Galzi, Jean‐Luc; Hibert, Marcel; Ilien, Brigitte

doi:10.1021/jm040800a

Cited by 95 publications

(149 citation statements)

References 39 publications

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“…The title compound results from our ongoing research aimed at the development of subtype-selective ligands for muscarinic receptors (Tahtaoui et al, 2004;Mohr et al, 2010). It was isolated as a side-product in the course of the synthesis of AFDX-type allosteric modulators of muscarinic M2 receptors (Mohr et al, 2004).…”

Section: Structure Descriptionmentioning

confidence: 99%

3-(2-Chloropyridin-3-yl)quinazoline-2,4(1H,3H)-dione chloroform monosolvate

2017

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The solvated title compound, C 13 H 8 ClN 3 O 2 ÁCHCl 3 , is a product of a condensation reaction between 2-amino-N-(2-chloropyridin-3-yl)benzamide and phosgene. The presence of the chlorine substituent in the pyridine ring forces the latter to adopt a nearly perpendicular orientation relative to the planar quinazoline ring (r.m.s. deviation = 0.04 Å ), the two ring systems being inclined to one another by 84.28 (9) . In the crystal, molecules are linked by pairs of N-HÁ Á ÁO hydrogen bonds, forming inversion dimers with an R 2 2 (8) ring motif. The dimers are linked by C-HÁ Á ÁO hydrogen bonds, forming ribbons propagating along the a-axis direction. The chloroform solvent molecules are linked to the organic molecule by C-HÁ Á ÁN hydrogen bonds. Structure descriptionThe title compound results from our ongoing research aimed at the development of subtype-selective ligands for muscarinic receptors (Tahtaoui et al., 2004;Mohr et al., 2010). It was isolated as a side-product in the course of the synthesis of AFDX-type allosteric modulators of muscarinic M2 receptors (Mohr et al., 2004). Specifically, the incomplete condensation between ethyl 2-aminobenzoate and 3-amino-2-chloropyridine (Holzgrabe & Heller, 2003) gave the ring-opened 2-amino-N-(2-chloropyridin-3-yl)-benzamide (1) in 23% yield. This compound, (1), was subjected to condensation with phosgene giving the title compound (2) in 85% yield. This two-step approach is of general interest for the synthesis of differently substituted (1H,3H)-quinazoline-2,4-diones.The molecular structure of the title compound (2), which crystallized as a chloroform monosolvate, is shown in Fig. 1. The pyridine ring (N1/C1-C5) is nearly perpendicular to the planar quinazoline ring (N2/N3/C6-C13; r.m.s. deviation = 0.04 Å ), making a dihedral angle of 84.28 (9) .

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Section: Structure Descriptionmentioning

confidence: 99%

3-(2-Chloropyridin-3-yl)quinazoline-2,4(1H,3H)-dione chloroform monosolvate

2017

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“…Atropine sulfate, NMS bromide, pirenzepine dihydrochloride, acetylcholine chloride, carbachol chloride, gallamine triethiodide, brucine sulfate, staurosporine, and WIN 51, Chemistry. Bo(12)Pz, Bo(15)Pz, and Bo(22)Pz fluorescent pirenzepine derivatives, together with the Bo(5) compound, were synthesized as reported (Tahtaoui et al, 2004). Their purity was checked by analytical reversed-phase high-performance liquid chromatography.…”

Section: Materials [mentioning

confidence: 99%

“…We previously reported on the synthesis and similar nanomolar affinity at muscarinic M1 receptors of a family (BoPz) of Bodipy pirenzepine derivatives, differing in length (10-22 atoms) of the linker connecting the Bodipy (558/568) fluorophore to the M1-selective antagonist (Tahtaoui et al, 2004). Fluorescence resonance energy transfer (FRET) studies performed on enhanced green fluorescent protein (EGFP)-fused M1 muscarinic receptors suggested the existence of two groups of molecules on the basis of linker length, donor (EGFP)-acceptor (Bodipy) distance in ligand-receptor complexes, and allosteric modulation.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the Orthosteric/Allosteric Interface in Human M1 Muscarinic Receptors by Bitopic Fluorescent Ligands

et al. 2013

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Bitopic binding properties apply to a variety of muscarinic compounds that span and simultaneously bind to both the orthosteric and allosteric receptor sites. We provide evidence that fluorescent pirenzepine derivatives, with the M1 antagonist fused to the boron-dipyrromethene [Bodipy (558/568)] fluorophore via spacers of varying lengths, exhibit orthosteric/ allosteric binding properties at muscarinic M1 receptors. This behavior was inferred from a combination of functional, radioligand, and fluorescence resonance energy transfer binding experiments performed under equilibrium and kinetic conditions on enhanced green fluorescent protein-fused M1 receptors. Although displaying a common orthosteric component, the fluorescent compounds inherit bitopic properties from a linkerguided positioning of their Bodipy moiety within the M1 allosteric vestibule. Depending on linker length, the fluorophore is allowed to reach neighboring allosteric domains, overlapping or not with the classic gallamine site, but distinct from the allosteric indolocarbazole "WIN" site. Site-directed mutagenesis, as well as molecular modeling and ligand docking studies based on recently solved muscarinic receptor structures, further support the definition of two groups of Bodipypirenzepine derivatives exhibiting distinct allosteric binding poses. Thus, the linker may dictate pharmacological outcomes for bitopic molecules that are hardly predictable from the properties of individual orthosteric and allosteric building blocks. Our findings also demonstrate that the fusion of a fluorophore to an orthosteric ligand is not neutral, as it may confer, unless carefully controlled, unexpected properties to the resultant fluorescent tracer. Altogether, this study illustrates the importance of a "multifacet" experimental approach to unravel and validate bitopic ligand binding mechanisms.

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“…25 The installation of a bis-BOC protected 3-guanidine group was achieved by treating 6 with N 1 ,N 2 -bis-(tertbutoxycarbonyl)-S-methylisothiourea (7), 26 to give the corresponding 3-guanidine phenyloxazole derivatives 8. Finally, on deprotection with trifluoroacetic acid, 3-guanidine phenyl oxazole derivatives 9 were obtained.…”

Section: Communicationmentioning

confidence: 99%

Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties

et al. 2013

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A series of functionalized phenyl oxazole derivatives was designed, synthesized and screened in vitro for their activities against LSD1 and for effects on viability of cervical and breast cancer cells, and in vivo for effects using zebrafish embryos. These compounds are likely to act via multiple epigenetic mechanisms specific to cancer cells including LSD1 inhibition.Histones are proteins that bind to DNA and facilitate efficient 'packing' of DNA in eukaryotic cells. 1 They are highly basic in nature due to the presence of positively charged amino acid side chains causing the DNA to fold around them into compact structures (nucleosomes). The ability of histones to regulate gene expression is controlled by post-translational modifications on the N-terminal (and likely C-terminal) "tails" of the core histones which project out of the nucleosome. Modifications including phosphorylation, acetylation, methylation, ubiquitination, sumoylation and biotinylation have been identified on the histone tails. 2 The cellular roles of histone lysine acetylation/deacetylation are the best characterized of the histone modifications -acetylation normally activates transcription whereas deacetylation deactivates this process. 3 Although there are clear links to disease, 4-8 the role of histone methylation is much less understood and appears to be context dependent.LSD1 (lysine specific demethylase 1) was the first histone demethylase identified. Its discovery significantly advanced the understanding of epigenetic regulation of gene expression, changing the paradigm that methylation is a non-reversible feature of histones. 9 Histone methylation/demethylation has since been found to be an important epigenetic modification linked to activation as well as repression of transcription. Two types of histone demethylases have been discovered. The flavin-dependent demethylase LSD1 acts on lysine 4 and lysine 9 of histone H3 (H3K4 and H3K9). LSD1 selectively catalyzes the oxidation of the methyl group of mono-and dimethylated lysines resulting in an imine intermediate and generation of hydrogen peroxide. The imine product is non-enzymatically hydrolysed to generate a carbinolamine resulting in demethylated lysine and formaldehyde release. 10 The other major class, i.e. Jumonji domain-containing histone demethylases, are Fe(II) and 2-oxoglutarate dependent oxygenases that act on mono-, di-and trimethylated Lys and methylated Arg residues depending on the particular enzymes. 11 Histone demethylase activity is associated with several pathological states. Increased LSD1 expression in prostate tumors correlates significantly with relapse during therapy. 6,7 Suppressed LSD1 expression is associated with vascular smooth muscle cell inflammatory damage in a mouse model of diabetes. 8 Demethylation of p53 (tumor suppressor) by LSD1 prevents p53 interaction with its co-activator 53BP1. 5 Activation of the telomerase reverse transcriptase (hTERT) gene is known to be dependent on LSD1 levels and recruitment to the hTERT promoter. 4 Studies on LSD1 hav...

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Fluorescent Pirenzepine Derivatives as Potential Bitopic Ligands of the Human M1 Muscarinic Receptor

Cited by 95 publications

References 39 publications

3-(2-Chloropyridin-3-yl)quinazoline-2,4(1H,3H)-dione chloroform monosolvate

3-(2-Chloropyridin-3-yl)quinazoline-2,4(1H,3H)-dione chloroform monosolvate

Exploration of the Orthosteric/Allosteric Interface in Human M1 Muscarinic Receptors by Bitopic Fluorescent Ligands

Synthesis and evaluation of 3-amino/guanidine substituted phenyl oxazoles as a novel class of LSD1 inhibitors with anti-proliferative properties

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