A5017637099- Mast cells and histamine
- Receptor Mechanisms and Signaling
- Phenothiazines and Benzothiazines Synthesis and Activities
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Neuroendocrine regulation and behavior
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Polyamine Metabolism and Applications
- Neurotransmitter Receptor Influence on Behavior
- Folate and B Vitamins Research
- Asthma and respiratory diseases
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Pharmacogenetics and Drug Metabolism
- Retinal Development and Disorders
- Synthesis and Biological Evaluation
- Allergic Rhinitis and Sensitization
- Mechanisms of cancer metastasis
- Click Chemistry and Applications
- Adenosine and Purinergic Signaling
- Genetic Syndromes and Imprinting
- Diet, Metabolism, and Disease
- Diet and metabolism studies
- Chemical synthesis and alkaloids
- Protein Kinase Regulation and GTPase Signaling
University of Copenhagen
2022-2024
Heinrich Heine University Düsseldorf
2018-2024
University of Pennsylvania
2017-2018
Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact biological targets relevant to the diseases, might offer an improved therapeutic alternative than using traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives a privileged scaffold for histamine H3 receptor (H3R). The most affine...
The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain (HA) acetylcholine (ACh), respectively. enzyme esterase (AChE) is involved in metabolism ACh. Both HA ACh are implicated several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, narcolepsy, all which comorbid with autistic spectrum disorder (ASD). Therefore, novel dual-active ligand E100 high H3R antagonist affinity (hH3R: Ki = 203 nM) balanced AChE inhibitory effect...
In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, kept mind that within the previous series, pair closely related compounds, KSK67 KSK68, differing only piperazine/piperidine moiety structural core showed significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, first focused an in-depth analysis protonation states...
Background and Purpose The dopamine D 2 receptor is expressed as a short (D2S) long (D2L) isoform with 29 additional amino acids in the third intracellular loop. D2S shows higher presynaptic expression than D2L isoform, decreased has recently been linked to an increased risk for schizophrenia. Here, we present first investigation, at level, of kinetic differences G protein activation profiles D2S, compared isoform. Experimental Approach We employed NanoBRET‐based approach dissociation...
While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability retention agonism. Here, we evaluate whether (B12-Ex4) can improve glucose tolerance without producing anorexia malaise.We evaluated effects systemic B12-Ex4...
Abstract Histamine H 3 receptors (H R), belonging to G‐protein coupled (GPCR) class A superfamily, are responsible for modulating the release of histamine as well other neurotransmitters by a negative feedback mechanism mainly in central nervous system (CNS). These have gained increased attention therapeutic target several CNS related neurological diseases. In current study, we aimed identify novel R ligands using silico virtual screening methods. To this end, combination ligand‐ and...
Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental characterized by social and communicative impairments, as well repetitive restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating behaviors, present study determined effects acute systemic treatment novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) dopamine D2/D3 affinity properties, on ASD-related RRBs male Black Tan BRachyury (BTBR)...
Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no molecules have shown successful results in clinical trials, thereby making common "one compound – one target" paradigm questionable. Recently, multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more treating AD. On basis these findings, we designed, synthesized,...
Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, series twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target PD based structure 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included introduction different cyclic amines and elongation alkyl...
Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3 Rs) and cholinesterases are involved in pathophysiology AD, identification dual-acting compounds capable improving cholinergic neurotransmission is importance AD pharmacotherapy. In the present study, R antagonistic activity combined with anticholinesterase properties two previously computationally identified lead compounds, that is,...
Abstract The role of epigenetic regulation is in large parts connected to cancer, but additionally, its therapeutic claim neurological disorders has emerged. Inhibition histone H3 lysine N -methyltransferase, especially G9a, been recently shown restore candidate genes from silenced parental chromosomes the imprinting disorder Prader–Willi syndrome (PWS). In addition this approach, pitolisant as G-protein coupled histamine H 3 receptor (H R) antagonist demonstrated promising effects for...
The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, novel series benzophenone derivatives was designed synthesized. Among these derivatives, we identified compound 6 with high H3R (Ki = 8 nM) significant activity toward BuChE (IC50 172 nM 1.16 µM eqBuChE hBuChE, respectively). Further in vitro studies...
In an attempt to find new dual acting histamine H3 receptor (H3R) ligands, we designed a series of compounds, structurally based on previously described in our group, highly active and selective human (hH3R) ligand KSK63. As result, 15 obtained compounds show moderate hH3R affinity, the best being compound 17 (hH3R Ki = 518 nM). Docking H3R homology model revealed two possible binding modes, with key interactions retained both cases. selected were tested for antioxidant properties. Compound...
The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H3 receptor (H3R) and MAO B can increase DA levels brain. A series compounds was designed tested vitro for human H3R (hH3R) affinity activity (hMAO B). Results showed different towards two biological targets. Most had poor hH3R (Ki > 500 nM), but very good potency hMAO (IC50 < 50 nM). After further testing (modality...