A5081248127- Receptor Mechanisms and Signaling
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Pharmacological Receptor Mechanisms and Effects
- Asymmetric Synthesis and Catalysis
- Click Chemistry and Applications
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and Biological Evaluation
- Monoclonal and Polyclonal Antibodies Research
- Cyclopropane Reaction Mechanisms
- Neuroscience and Neuropharmacology Research
- Synthetic Organic Chemistry Methods
- Chemical synthesis and alkaloids
- Synthesis and Reactivity of Heterocycles
- Fluorine in Organic Chemistry
- Analytical Chemistry and Chromatography
- Synthesis and Catalytic Reactions
- Computational Drug Discovery Methods
- Photochromic and Fluorescence Chemistry
- Synthesis and pharmacology of benzodiazepine derivatives
- Carbohydrate Chemistry and Synthesis
- Mass Spectrometry Techniques and Applications
- Pharmacological Effects and Assays
- Biochemical Analysis and Sensing Techniques
- Oxidative Organic Chemistry Reactions
Friedrich-Alexander-Universität Erlangen-Nürnberg
2016-2025
Forschungsinstitut für Anwendungsorientierte Wissensverarbeitung
2024
Fischer (Germany)
2009-2021
Institute of Medicinal Plant Development
2019
International Neuromodulation Society
2019
Freie Universität Berlin
2013
Stanford University
2013
National Institute of Diabetes and Digestive and Kidney Diseases
2013
University of California, San Francisco
2013
University of Toronto
2013
Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α
Starting from dopamine receptor ligand BP897, an interactive drug discovery process leading to heterocyclic bioisosteres is demonstrated. The four step strategy involved a careful optimization of geometric and electronic properties by systematic modification the attachment points heteroatoms, respectively. Efficacy tuning phenyl substituents led both D3 partial agonists full antagonists. benzothiophenes 3c (FAUC346) 3d (FAUC365) revealed outstanding affinity subtype selectivity.
G-protein-coupled receptors (GPCRs) represent the largest family of membrane proteins involved in cellular signal transduction and are activated by various different ligand types including photons, peptides, proteins, but also small molecules like biogenic amines. Therefore, GPCRs diverse physiological processes provide valuable drug targets for numerous diseases. Emerging body evidence suggests that exist as monomers or cross-react forming dimers higher-ordered oligomers. In this...
Abstract G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation receptor D 2 homodimers has been suggested to be associated with the pathophysiology schizophrenia. Selective labeling and ligand-induced modulation dimerization may therefore allow investigation pathophysiological role these dimers. Using TIRF microscopy at single molecule level, transient in membrane stably transfected CHO cells...
Abstract Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis biological investigations bivalent ligands for dopamine D 2 receptor/neurotensin NTS 1 (D R/NTS R) heterodimers. The compounds types 1–3 consist three different R pharmacophores bound to an affinity-generating lipophilic appendage, polyethylene glycol-based linker agonist NT(8-13). show...
Abstract The μ‐opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well β‐arrestin recruitment. agonists that are biased towards demonstrate diminished side effects. PZM21, discovered by computational docking, a agonist. Here we report cryoEM structure PZM21 bound in complex with i protein. Structure‐based evolution led to multiple analogs more pronounced bias and increased lipophilicity improve CNS penetration....
Abstract The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled (GPCR) that serves as model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) NMR spectroscopy, focusing on physiological agonist acetylcholine supra-physiological iperoxo, well positive modulator LY2119620. These studies reveal stabilizes more heterogeneous...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to fibrosis, whereas its hyperactivation secretory diarrhea. Small molecules that improve CFTR folding (correctors) or (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet be developed. Here, we combine molecular docking, electrophysiology, cryo-EM, medicinal chemistry identify modulators. We...
Schizophrenia is a chronic and severe mental disorder. It currently treated with antipsychotic drugs (APD). However, APD's work only in limited number of patients may have cognition impairing side effects. A growing body evidence points out the potential involvement abnormal sphingolipid metabolism pathophysiology schizophrenia. Here, an analysis human gene polymorphisms brain expression schizophrenia identified association SMPD1 SMPD3 genes coding for acid- (ASM) neutral sphingomyelinase-2...
To evaluate nonaromatic catechol bioisosteres, the conformationally restrained enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupling as key reaction step. Subsequent receptor binding studies at dopamine subtypes D1, D2 long, short, D3, D4 showed highly interesting profiles for 1a 1b when compared to dopamine. At guanine nucleotide-sensitive high-affinity site of D3 receptor, target compound (Ki = 5.2 nM) was 10-fold more potent than but less subtypes. In contrast...
[reaction: see text] Highly efficient methodology for the construction of functionalized resins was presented involving 1,3-dipolar cycloaddition as key reaction step. On basis this concept, first series click backbone amide linkers were synthesized and application FIMT resin 3f to parallel synthesis putative dopaminergic agents demonstrated leading selective receptor ligands 10i 10s revealing high affinity D4 subtype.
Click for PET: An efficient strategy based on click chemistry has been developed 18F-labeling alkyne-bearing peptides with concomitant glycosylation. The mild conditions and general applicability of this reliable reaction gives access to a new class 18F-glycopeptide radiopharmaceuticals improved biological properties in vivo imaging studies by positron emission tomography (PET). Detailed facts importance specialist readers are published as "Supporting Information". Such documents...
Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these drug targets. However, crystallization GPCRs in active states is particularly challenging, requiring formation stable conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, synthetic agonists that bind with low affinity are ineffective at stabilizing an state for crystallogenesis. To promote structural pharmacologically highly...
Significance The development of selective antagonists for muscarinic acetylcholine receptors is challenging due to high homology in orthosteric binding sites among subtypes. Starting from a single amino acid difference the pockets M2 receptor (M2R) and M3R, we developed an M3R-selective antagonist using molecular docking structure-based design. resulting M3R showed up 100-fold selectivity over M2R affinity 1,000-fold vivo. docking-predicted geometry was further confirmed by 3.1 Å crystal...