Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors

Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition: a biomarker axis in stress‐induced cognitive and emotional impairment

“…This feature is highly relevant for developing a novel class of steroid‐based NMDA‐inhibitor therapeutics, which lack the side effects that plague the use of classical NMDA receptor inhibitors, including ketamine and congeners. Based on this mechanism of action, a number of PAS analogues have been recently synthesized, including the amide‐based analogues (Adla et al, ) and pregnanolone hemipimelate that has no action at phasic and synaptic NMDA receptors but shows a strong selectivity (several folds higher than PAS) in inhibiting tonic‐activated receptors (Vyklicky et al, ).…”

Strong Inhibitory Effect, Low Cytotoxicity and High Plasma Stability of Steroidal Inhibitors of N-Methyl-D-Aspartate Receptors With C-3 Amide Structural Motif

“…Compound 13 was prepared according to the literature: ( Adla et al, 2017 ) in brief, commercially available 3β-hydroxy-5β-androstane was treated with phthalimide and triphenylphosphine, followed by deprotection of the amino group in hydrazine hydrate, to give 3α-amino derivative 13. Compounds 1 and 2 were prepared according to the literature ( Adla et al, 2017 ) by treatment of compound 13 with the monoethyl ester of oxalic acid and methyl 3-chloro-3-oxopropionate, respectively, followed by basic hydrolysis. Analogously, compounds 3 and 4 were prepared by treatment of compound 13 with methyl 4-chloro-4-oxobutyrate and methyl 5-chloro-5-oxovalerate, respectively, affording compounds 14 in 79% and 15 in 83% yield.…”

“…Deprotection of the benzyl ether protecting group was achieved by hydrogenation catalyzed by palladium on carbon (compound 5, 65% yield and 7, 98% yield). Then, treatment of Boc-protected aspartate 5 and glutamate 7 with trifluoroacetic acid gave desired products 6 and 8 in 91% and 92% yield, respectively ( Adla et al, 2017 ).…”

“…From our previous studies, ( Borovska et al, 2012 ; Kudova et al, 2014 , 2015 ; Adla et al, 2017 ) we proposed that amide PAG-like compounds (1–12) offer a promising target for synthesis, further development and complex evaluation of physicochemical and biological properties including the screening on their stability in plasma. As such, compounds 1–12 were evaluated on HEK293 cells transfected with plasmids encoding GluN1-1a/GluN2B/GFP genes to elucidate the SAR of the amide, amino, and Boc-protected amino moiety in various positions.…”

Visualizing pregnenolone sulfate-like modulators of NMDA receptor function reveals intracellular and plasma-membrane localization

“…An unexpected outcome of the work was the identification of potent and efficacious analogues (Figure 1), which suggest new aspects of the structure-activity relationship between steroids and NMDARs. Previous work has explored mostly steroid inhibitors of NMDAR function (Adla et al, 2017). Based on the strong activity of multiple analogues with a hydrophobic side chain, we conclude that side chain hydrophobicity is likely to increase potentiation.…”