Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines

Lemaître, Stéphane; Lepailleur, Alban; Bureau, Ronan; Butt‐Gueulle, Sabrina; Lelong‐Boulouard, Véronique; Duchatelle, Pascal; Boulouard, Michel; Dumuis, Aline; Daveu, Cyril; Lezoualc’h, Frank; Pfeiffer, Bruno; Dauphin, François; Rault, Syl­vain

doi:10.1016/j.bmc.2008.11.045

Cited by 17 publications

(17 citation statements)

References 48 publications

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“…The system is a tool for identifying perturbagens whose overall effect in gene expression either mimics or reverses the gene expression pattern. When provided with the differentially expressed (up & down-regulated) proteins of Comparison G1 vs. G2 and asked to return the agents that most efficiently reversed that phenotype, the top hit was BRD-K01868942 (Supplementary Table 9 ), a novel serotonin receptor antagonist (Lemaître et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population

et al. 2018

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The composition of the salivary proteome is affected by pathological conditions. We analyzed by high resolution mass spectrometry approaches saliva samples collected from children and adolescents with type 1 diabetes and healthy controls. The list of more than 2000 high confidence protein identifications constitutes a comprehensive characterization of the salivary proteome. Patients with good glycemic regulation and healthy individuals have comparable proteomic profiles. In contrast, a significant number of differentially expressed proteins were identified in the saliva of patients with poor glycemic regulation compared to patients with good glycemic control and healthy children. These proteins are involved in biological processes relevant to diabetic pathology such as endothelial damage and inflammation. Moreover, a putative preventive therapeutic approach was identified based on bioinformatic analysis of the deregulated salivary proteins. Thus, thorough characterization of saliva proteins in diabetic pediatric patients established a connection between molecular changes and disease pathology. This proteomic and bioinformatic approach highlights the potential of salivary diagnostics in diabetes pathology and opens the way for preventive treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population

et al. 2018

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“…In vivo, it exhibited significant antinociceptive activity in the mouse writhing test at doses of 0.1-1 mg/kg i.p. The pyrrolothienopyrazine 133 [189,190] is a less selective derivative (pIC 50 = 9.16 for 5-HT 4 R and 8.16 for 5-HT 3 R) and acts as an antagonist / weak partial agonist in COS-7 cells (5-HT 4(a) R).…”

Section: Benzamide Derivatives (Figs 2425)mentioning

confidence: 99%

Review of 5-HT4R Ligands: State of Art and Clinical Applications

Bureau¹,

Boulouard²,

Dauphin³

et al. 2010

CTMC

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This article reviews the medicinal implications of 5-HT(4)R in the peripheral and central nervous systems, based on data from two hundred bibliographic references. An exhaustive compilation of molecules reported to be antagonists or agonists for 5-HT(4)R is presented, including chemical structures, binding properties and pharmacological profiles. In the last part of the review, some key concepts concerning structure-activity relationships are highlighted.

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“…For the iodinated side chain, we chose to add a terminal iodoaryl group to the propyl chain. 25,26 Thus, 10 was prepared starting from 4-iododihydrocinnamic acid involving amidation with ethyl isonipecotate and reduction of both the carboxamide and ester function with diisobutylaluminium hydride (Scheme 2). …”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure–Affinity Relationships of Selective High-Affinity 5-HT₄ Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers

Dubost

Dumas²,

Fossey

et al. 2012

J. Med. Chem.

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The work described herein aims at finding new potential ligands for the brain imaging of 5-HT4 receptors using single-photon emission computed tomography (SPECT). Starting from the non-substituted phenanthridine compound 4a exhibiting a Ki value of 51 nM on 5-HT4R, we explored structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to increase both the affinity and the selectivity for 5-HT4R suggesting the design of the antagonist 4v exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT4R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[123I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate ([123I]1, [123I]SB 207710) both in vitro and in vivo in brain. Compound 11d was radiolabeled with [125I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT4R.

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Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines

Cited by 17 publications

References 48 publications

Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population

Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population

Review of 5-HT4R Ligands: State of Art and Clinical Applications

Synthesis and Structure–Affinity Relationships of Selective High-Affinity 5-HT₄ Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers

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Novel antagonists of serotonin-4 receptors: Synthesis and biological evaluation of pyrrolothienopyrazines

Cited by 17 publications

References 48 publications

Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population

Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population

Review of 5-HT4R Ligands: State of Art and Clinical Applications

Synthesis and Structure–Affinity Relationships of Selective High-Affinity 5-HT4 Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers

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Product

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Synthesis and Structure–Affinity Relationships of Selective High-Affinity 5-HT₄ Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers