Tritium‐Labeled Brivaracetam with High Specific Activity: Preparation, Characterization and Application in Human Brain Samples

Hildenbrand, Simone; Schoch, Susanne; Lehe, Marec von; Surges, Rainer; Müller, Christian

doi:10.1002/cmdc.201200183

Cited by 7 publications

(1 citation statement)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The competitive radioligand-binding assay was essentially performed as previously described. , The SV2A-containing preparations, either cell lysate of human SV2A-expressing CHO cells, or membrane preparations of mouse brain cortex, were incubated with the radioligand [ 3 H]brivaracetam (3 nM) in the absence or presence of test compound for 4 h. Incubation was performed in 500 μL of Tris-buffer (50 mM Tris–HCl, pH 7.4) containing 2 mM MgCl 2 at 4 °C on a rocking shaker. Nonspecific binding was determined in the presence of 1 mM levetiracetam.…”

Section: Methodsmentioning

confidence: 99%

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

et al. 2022

Self Cite

View full text Add to dashboard Cite

( R )-7 [ ( R )-AS-1 ] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. ( R )-7 [ ( R )-AS-1 ] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, ( R )-7 [ ( R )-AS-1 ] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.

show abstract

Section: Methodsmentioning

confidence: 99%

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Glyoxylic Acid

Reddy

Cook

et al. 2014

Encyclopedia of Reagents for Organic Synthesis

View full text Add to dashboard Cite

Interaction of Approved Drugs with Synaptic Vesicle Protein 2A

Danish

Namasivayam

Schiedel

et al. 2017

Archiv der Pharmazie

View full text Add to dashboard Cite

Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti‐epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [3H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration–inhibition curves revealed the antihistaminic prodrug loratadine (Ki = 1.16 μM) and the antimalarial drug quinine (Ki = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (Ki = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure–activity relationships were determined. The anti‐convulsive effects of the natural product quinine may – at least in part – be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti‐epileptic drug development.

show abstract

Tritium‐Labeled Brivaracetam with High Specific Activity: Preparation, Characterization and Application in Human Brain Samples

Cited by 7 publications

References 19 publications

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

Glyoxylic Acid

Interaction of Approved Drugs with Synaptic Vesicle Protein 2A

Contact Info

Product

Resources

About