- Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based GluN2B receptor antagonists
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Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11, 12, 14, and 15 were synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [3H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol 15 (Ki = 193 nM) bearing a p-fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of 15 showing moderate σ2 affinity (Ki = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ1 and σ2 receptors was rather low (Ki > 100 nM).
- Wagner, Marina,Schepmann, Dirk,Ametamey, Simon M.,Wünsch, Bernhard
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supporting information
p. 3559 - 3567
(2019/07/03)
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- Click chemistry based synthesis of dopamine D4 selective receptor ligands for the selection of potential PET tracers
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Taking advantage of click chemistry, a library of N-arylpiperazinylmethyl triazoles bearing fluoro substituted appendages was synthesized and the target compounds were investigated for dopamine and serotonin receptor binding. With the aim to bias their hydrophilicity and to optimize their D4 receptor affinity and selectivity, a concise series of triazoles containing fluoroalkyl, fluoroalkoxy, fluoroalkoxyphenyl, and deoxyfluoroglucosyl substituents was studied. The D4 receptor affinity and selectivity could be tuned by altering the chemical moiety attached to the triazole unit. Among the test compounds, the fluoroethoxyphenyl derivative 15b showed weak partial agonism at D4 and a K i value of 14 nM, while its fluoropropoxyphenyl homologue 16a turned out to act as a neutral D4 antagonist (Ki = 5.1 nM). Both, 15b and 16a revealed an excellent balance between D4 receptor affinity and subtype selectivity, providing lead candidates for the development of 18F-labeled radioligands for D4 receptor imaging studies by positron emission tomography (PET).
- Banerjee, Ashutosh,Maschauer, Simone,Hübner, Harald,Gmeiner, Peter,Prante, Olaf
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p. 6079 - 6082
(2013/11/06)
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- Pesticidal 2-fluoroethyl ethers
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Pesticidal mono-, di-, and tri-2-fluoroethyl ethers of the formula R1 R2m Ar(OCH2 CH2 F)n, compositions thereof and their insecticidal, acaricidal and nematicidal uses are described and cla
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