Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders

Espadinha, Margarida; Viejo, Lucía; Lopes, Ricardo; Herrera-Arozamena, Clara; Molins, Elı́es; Santos, Daniel Terrón; Gonçalves, Lídia; Rodríguez‐Franco, María Isabel; Rı́os, Cristóbal de los; Santos, Maria M. M.

doi:10.1016/j.ejmech.2020.112242

Cited by 2 publications

(4 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The spectral data obtained for compounds 7j and 7j' indicate that the major diastereomer 7j has (3R, 7aR, 7S) configuration, while the minor diastereoisomer 7j' has (3R, 7aR, 7R) configuration [21]. In particular, the methyl group appears in the 1 H NMR spectra as a doublet at 1.12 ppm for 7j and at 0.60 ppm for 7j', and in the 13 C NMR spectra at 13.96 ppm for 7j and at 16.40 ppm for 7j'.…”

Section: Chemistrymentioning

confidence: 95%

“…Other reagents were obtained from commercial suppliers (Sigma-Aldrich, Alfa Aesar, and Fluorochem). General information concerning the equipment used for the elucidation of the products' chemical structures and product characterization (NMR, melting point, optical rotations, MS, and elemental analysis) are presented in our earlier publication [21]. Multiplicities in 1 H NMR spectra are given as: s (singlet), d (doublet), dd (double doublet), ddd (doublet of doublets of doublets), t (triplet), and m (multiplet).…”

Section: Chemistrymentioning

confidence: 99%

See 1 more Smart Citation

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring.

show abstract

Section: Chemistrymentioning

confidence: 95%

Section: Chemistrymentioning

confidence: 99%

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor, is crucial for regulating the physiology and normal function of the central nervous system (Witkin et al, 2021). Numerous psychiatric and neurodegenerative disorders are associated with the overactivation of the NMDA receptor (Espadinha et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The N ‐methyl‐ d ‐aspartate (NMDA) receptor, an ionotropic glutamate receptor, is crucial for regulating the physiology and normal function of the central nervous system (Witkin et al, 2021). Numerous psychiatric and neurodegenerative disorders are associated with the overactivation of the NMDA receptor (Espadinha et al, 2020). Recent reports have shown that NMDA receptor antagonists act as potential antidepressants with rapid onset (Adell, 2020; Chen et al, 2020; Meshkat et al, 2022; Morris et al, 2021; Pochwat et al, 2019; Swainson et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ‐14, a novel N‐methyl‐d‐aspartate receptor antagonist, in rats by liquid chromatography–tandem mass spectrometry

Huang,

Zhang,

Yang

et al. 2024

Biomedical Chromatography

View full text Add to dashboard Cite

To circumvent the limitations of current antidepressants, WJ‐14, a novel N‐methyl‐d‐aspartate receptor antagonist, was synthesized and demonstrated to have remarkable efficiency in the treatment of depression. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of WJ‐14 in rats, a rapid and sensitive liquid chromatography–tandem mass spectrometry–based analytical method was developed and validated for the separation and detection of WJ‐14 in both plasma and tissue samples. After oral administration, WJ‐14 was rapidly absorbed into the blood with time to reach the maximum plasma concentration (Tmax) within 0.28 h and quickly eliminated with clearance (Cl) exceeding 6.80 L/h/kg and elimination half‐life (t1/2) within 2.69 h. No obvious accumulation was found with mean residencetime (MRT) within 4.10 h. Tissue distribution revealed that WJ‐14 was extensively distributed in the main tissues of rats, and massive amounts of WJ‐14 were distributed in the liver. Extensive distribution and quick elimination led to extremely low absolute bioavailability of WJ‐14 (1.91% of 8.33 mg/kg and 3.30% of 24.99 mg/kg). WJ‐14 was detected in the brain only 0.083 h after oral administration, which is crucial for a rapid‐onset antidepressant candidate. In addition, WJ‐14 likely exhibited a non‐linear pharmacokinetic process at dosages of 8.33 and 24.99 mg/kg. The findings may provide valuable information for subsequent studies on WJ‐14.

show abstract

Identification of tetracyclic lactams as NMDA receptor antagonists with potential application in neurological disorders

Cited by 2 publications

References 50 publications

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

Pharmacokinetics, absolute bioavailability, and tissue distribution of WJ‐14, a novel N‐methyl‐d‐aspartate receptor antagonist, in rats by liquid chromatography–tandem mass spectrometry

Contact Info

Product

Resources

About