+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold

Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold

Bioorganic and Medicinal Chemistry Letters 26(3): 889-893

In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3-benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3 induced elimination of trifluoromethanelsulfinate (F3CSO2(-)). In receptor binding studies with the radioligand [(3)H]ifenprodil the 3-benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar.

(PDF emailed within 0-6 h: $19.90)

Accession: 058791447

Download citation: RISBibTeXText

PMID: 26750254

DOI: 10.1016/j.bmcl.2015.12.067

Related references

Pharmacokinetic properties of enantiomerically pure GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold. Journal of Pharmaceutical and Biomedical Analysis 172: 214-222, 2019

Replacement of benzylic hydroxy group by vinyl or hydroxymethyl moiety at the 3-benzazepine scaffold retaining GluN2B affinity. Bioorganic and Medicinal Chemistry 25(20): 5365-5372, 2017

Fluorinated GluN2B Receptor Antagonists with a 3-Benzazepine Scaffold Designed for PET Studies. Chemmedchem 13(10): 1058-1068, 2018

Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation. European Journal of Medicinal Chemistry 144: 672-681, 2018

Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B-Selective NMDA Receptor Antagonists with a Benzo[7]annulen-7-amine Scaffold. Chemmedchem 12(15): 1212-1222, 2017

Deconstruction - reconstruction approach to analyze the essential structural elements of tetrahydro-3-benzazepine-based antagonists of GluN2B subunit containing NMDA receptors. European Journal of Medicinal Chemistry 138: 552-564, 2017

Pyridine bioisosteres of potent GluN2B subunit containing NMDA receptor antagonists with benzo[7]annulene scaffold. European Journal of Medicinal Chemistry 157: 397-404, 2018

Benzimidazolone bioisosteres of potent GluN2B selective NMDA receptor antagonists. European Journal of Medicinal Chemistry 116: 136-146, 2017

2-Methyltetrahydro-3-benzazepin-1-ols - The missing link in SAR of GluN2B selective NMDA receptor antagonists. Bioorganic and Medicinal Chemistry 26(2): 501-508, 2017

A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists. Molecular Pharmacology 89(5): 541-551, 2016

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists. Chemmedchem 13(15): 1580-1587, 2018

Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen-7-amines as GluN2B-selective NMDA receptor antagonists. Journal of Labelled Compounds and Radiopharmaceuticals 2019, 2019

Novel GluN2B selective NMDA receptor antagonists: relative configuration of 7-meth-oxy-2-methyl-2,3,4,5-tetra-hydro-1H-3-benzazepin-1-ols. Acta Crystallographica. Section E, Crystallographic Communications 72(Pt 5): 687-691, 2016

Benzo[7]annulene-based GluN2B selective NMDA receptor antagonists: Surprising effect of a nitro group in 2-position. Bioorganic and Medicinal Chemistry Letters 25(24): 5748-5751, 2016

Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor. Journal of Nuclear Medicine 2018, 2018