A5054958814- Neuroscience and Neuropharmacology Research
- Chemical Synthesis and Analysis
- Biochemical effects in animals
- Advanced Biosensing Techniques and Applications
- Advanced Proteomics Techniques and Applications
- Computational Drug Discovery Methods
- GABA and Rice Research
- Drug Transport and Resistance Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Amino Acid Enzymes and Metabolism
- Analytical Chemistry and Sensors
- DNA and Nucleic Acid Chemistry
- Tryptophan and brain disorders
- Pharmacological Effects and Toxicity Studies
- Electrochemical sensors and biosensors
- Bioinformatics and Genomic Networks
- Ion channel regulation and function
- Antimicrobial Peptides and Activities
- HIV/AIDS drug development and treatment
- Cardiomyopathy and Myosin Studies
- Electrochemical Analysis and Applications
- Pharmacological Receptor Mechanisms and Effects
- Mitochondrial Function and Pathology
- Phosphodiesterase function and regulation
- Immune cells in cancer
University of Copenhagen
2021-2025
University of Vienna
2017-2025
The calcium/calmodulin-dependent protein kinase II alpha (CaMKIIa) is a highly important synaptic protein, which comprises unique holoenzyme structure organized via the central hub domain. Recently, distinct binding pocket in CaMKIIa domain was identified for endogenous neuromodulator g-hydroxybutyric acid (GHB) and related synthetic analogues. Key interacting residues CaMKII were revealed, but pronounced selectivity towards variant of has remained unresolved. Aimed at elucidating molecular...
The Ca2+/CaM-dependent protein kinase II alpha (CaMKIIα) is a highly important synaptic protein, which comprises unique holoenzyme structure organized via the central hub domain. Recently, distinct binding pocket in CaMKIIα domain was identified for endogenous neuromodulator γ-hydroxybutyric acid (GHB) and related synthetic analogues. Intriguingly, of four native CaMKII isozymes, only accommodates GHB ligands. Key interacting residues were revealed, but their involvement selectivity towards...
ABSTRACT The serotonin transporter (SERT) belongs to the family of neurotransmitter sodium symporters (NSS), together with other transporters for norepinephrine, dopamine, glycine, and GABA. main physiological role SERT is retrieval previously released from synaptic cleft. Thereby, plays an important in regulating extracellular concentration maintaining serotonergic neurotransmission. This process can be influenced by molecules acting as uptake inhibitors, like paroxetine. Here, we report...
N-(1-Benzyl-4-piperidinyl)-2,4-dichlorobenzamide 5 (BPDBA) is a noncompetitive inhibitor of the betaine/GABA transporter 1 (BGT1). We here report synthesis and structure–activity relationship 71 analogues. identify 26m as more soluble 2,4-Cl substituted 3-pyridine analogue with retained BGT1 activity an improved off-target profile compared to 5. performed radioligand-based uptake studies at chimeric constructs between GAT3, experiments site-directed mutated transporters, computational...
Inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA) plays an important role in maintaining body homeostasis. Disturbances GABA signaling are implicated a multitude of neurologic and psychiatric conditions, including epilepsy, ischemia, anxiety, depression, insomnia, mood disorders. Clinically relevant increases neurotransmitter level can be achieved inhibition its uptake into presynaptic neurons surrounding glial cells, driven transporters (GAT1, BGT1, GAT2, GAT3). Herein, we...
Focal epileptic seizures can in some patients be managed by inhibiting γ-aminobutyric acid (GABA) uptake via the GABA transporter 1 (GAT1) using tiagabine (Gabitril®). Synergistic anti-seizure effects achieved inhibition of both GAT1 and betaine/GABA (BGT1) EF1502, compared to alone, suggest BGT1 as a target epilepsy. Yet, selective inhibitors are needed for validation this hypothesis. In that search, series typified...
Abstract The activity and potency of a drug is inherently affected by the metabolic state its target cell. Solute Carriers (SLCs) represent largest family transmembrane transporters in humans constitute major determinants cellular metabolism. Several SLCs have been shown to be required for uptake individual chemical compounds into systems, but systematic surveys transporter-drug relationships human cells are currently lacking. We performed series genetic screens haploid cell line HAP1 using...
Abstract We have previously identified 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA) as the most potent substrate-inhibitor of betaine/GABA transporter 1 (BGT1) (IC 50 2.5 µM) reported to date. Herein, we characterize binding mode 20 novel analogs and propose molecular determinants driving BGT1-selectivity. A series N -, exocyclic- C 4 -substituted was synthesized pharmacologically characterized in radioligand-based uptake assays at four human GABA transporters (hGATs)...
The betaine/GABA transporter 1 (BGT1) is a member of the GABA (GAT) family with still elusive function, largely due to lack potent and selective tool compounds. Based on modeling, we here present design, synthesis pharmacological evaluation five novel conformationally restricted cyclic analogs related previously reported highly BGT1 inhibitor (1 S ,2 ,5 R )-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [ 3 H]GABA radioligand uptake assays at four human GATs...
Abstract Proteochemometric modeling (PCM) combines ligand information as well target in order to predict an output variable of interest (e.g. activity a compound). The big advantage PCM compared conventional Quantitative Structure-Activity Relationship (QSAR) is, that by creating single model one can not only the affinity diverse set compounds targets, but also extrapolate specific ligand-protein interactions might be relevant for activity. In this study, we compiled dataset 323 and their...
Abstract The GABA transporter 3 (GAT3) is a member of the (GAT) family proposed to have role in regulating tonic inhibition. GAT3-preferring substrate ( S )-isoserine has shown beneficial effects mouse model stroke accompanied by an increased GAT3 expression, indicating molecular mechanism mediated GAT3. However, not ideally suited for vivo studies due lack selectivity and brain permeability. To elucidate structural determinants inhibition, optimize inform further ligand development, we here...