Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

Banerjee, Ashutosh; Schepmann, Dirk; Köhler, Jens; Würthwein, Ernst‐Ulrich; Wünsch, Bernhard

doi:10.1016/j.bmc.2010.09.047

Cited by 44 publications

(31 citation statements)

References 25 publications

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“…In addition to high subtype selectivity, both 1,4‐diazepanes ( S )‐ 20a and ( S )‐ 21b do not interact with the PCP binding site of the NMDA receptor up to a concentration of 10 μM, indicating high selectivity for the σ 1 receptor over the PCP binding site.…”

Section: Resultsmentioning

confidence: 99%

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Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Fanter

Schepmann

Wünsch

2017

Archiv der Pharmazie

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The aim of this work was to transfer the established chiral-pool synthesis of 1,2, 4-trisubstituted 1,4-diazepanes in solution on the solid phase. For this purpose, (S)-configured amino acids, (S)-alanine, and (S)-leucine, with a small methyl and a larger isobutyl moiety were attached to the solid support 9 by reductive amination. After five reaction steps on the solid support, the 1,4-diazepanes (S)-19a,b were cleaved off and reductively alkylated to afford the 1,2,4-trisubstituted 1,4-diazepanes (S)-20a and (S)-21b, respectively. Both compounds show high σ 1 affinity and selectivity over the σ 2 subtype. K E Y W O R D S1,2,4-trisubstituted 1,4-diazepanes, σ 1 receptor ligands, chiral-pool synthesis, solid-phase organic synthesis, subtype selectivity

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Section: Resultsmentioning

confidence: 99%

“…The affinity of the synthesized 1,4‐diazepanes toward σ 1 and σ 2 receptors was recorded as described in refs . The affinity toward the PCP binding site of the NMDA receptor was recorded as reported in refs …”

Section: Methodsmentioning

confidence: 99%

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Fanter

Schepmann

Wünsch

2017

Archiv der Pharmazie

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“…Pig brain membrane preparations were used as receptor material. [22][23][24] The affinity data of the propellanamines 3 and reference compounds are summarized in Table 1.…”

Section: Biological Activitymentioning

confidence: 99%

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Torres‐Gómez

Lehmkuhl

Frehland

et al. 2015

Bioorganic & Medicinal Chemistry

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“…To characterize the fluoroethoxy derivatives 14, 17,a nd 18 in greater detail,t he affinity for the phencyclidine (PCP) binding site within the channel pore of the NMDA receptor [30,31] and the affinity for both s receptor subtypes [32][33][34] were determined in radioligand receptor binding studies. Up to ac oncentrationo f1mm the test compounds did not compete with the radioligand [ 3 H]MK-801f or the PCP binding site, indicating very low PCP affinity and thus high selectivity for the ifenprodil binding site (Table 1).…”

Section: Selectivity Against Related Bindingsites and Receptorsmentioning

confidence: 99%

Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies

et al. 2018

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To analyze the N-methyl-d-aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B-subunit-containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1,7-diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7-position), 17 (9-position), 18a-c (1-position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [ F]14 was performed by nucleophilic substitution of the phenol 2 with 2-[ F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [ F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981, and the non-labeled 3-benzazepine 14 were able to abolish the specific binding of [ F]14.

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Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

Cited by 44 publications

References 25 publications

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies

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Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

Cited by 44 publications

References 25 publications

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ1 receptor affinity

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ1 receptor affinity

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies

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Product

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Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity

Solid‐phase organic synthesis of chiral, non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ₁ receptor affinity