Discovery of 7,9-Dibromo-dihydrodibenzofuran as a Potent Casein Kinase 2 (CK2) Inhibitor: Synthesis, Biological Evaluation, and Structural Studies on /-Isomers.

The human protein kinase CK2 is a promising target for cancer treatment. Only two CK2 inhibitors have reached clinical trials until today. Among others, a dibenzofuran scaffold has emerged as highly prospective for the development of new CK2 inhibitors.

Synthesis and structure-affinity relationships of spirocyclic σ receptor ligands with tetrahydropyran scaffold.

The σ receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ receptor affinity and selectivity over related targets. The σ affinity of the ligands was correlated with their lipophilicity (logD value) giving insight into their lipophilic ligand efficiency (LLE).

Enantiomerically Pure Indazole Bioisosteres of Ifenprodil and Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors with the GluN2B Subunit.

Administration of negative allosteric modulators of GluN2B subunit-containing NMDA receptors such as Ro 25-6981 () and ifenprodil () results in neuroprotective effects. In this study, the phenol of and was replaced bioisosterically by an indazole to inhibit glucuronidation. The γ- and β-aminoalcohols and were prepared without installing a protective group at the indazole ring using the ketone as a common intermediate.

Two-Step Synthesis of Enantiomerically Pure Morphans from (R)-Carvone.

Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold.

A novel fluorescent labeling compound for GluN2A containing -methyl-d-aspartate receptors identified by autodisplay-based screening.

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Quinolone bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists.

Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight-step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel-Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β-unsaturated ketone 12a.

N-Pyrazolyl- and N-Triazolylamines and -Ureas as Antileishmanial and Antitrypanosomal Drugs.

Three types of modifications of antileishmanial pyrazole lead compounds 7 and 8 were conducted to expand understanding of the relationships between structural features and antileishmanial/antitrypanosomal activity: (1) the pyrazole core was retained or replaced by a 1,2,4-triazole ring; (2) various aryl moieties including 2-fluorophenyl, pyridin-3-yl and pyrazin-2-yl rings were attached at 3-position of the core azole; (3) either arylmethylamino or ureido substituents were introduced at 5-position of the azole core. The synthesis followed established routes starting with esters 9 or 15 and anhydride 21. The synthesized 3-arylpyrazoles and 3-aryl-1,2,4-triazoles had only very low antileishmanial activity.

[F]Fluspidine-A PET Tracer for Imaging of σ Receptors in the Central Nervous System.

σ receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer's disease, and depression. Spirocyclic piperidines represent a promising class of potent σ receptor ligands. The relationship between structural modifications and σ receptor affinity and selectivity over σ receptors led to the 2-fluoroethyl derivative fluspidine (, = 0.

Late-Stage Diversification of Pyrazoles as Antileishmanial Agents.

N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage diversification of 3-bromopyrazoles 10 A/B and 14 A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electron-withdrawing properties of the cyano moiety in 4-position of the pyrazole ring limited the acylation of the primary amino moiety in 5-position.

Sigma receptor and aquaporin modulators: chiral resolution, configurational assignment, and preliminary biological profile of RC752 enantiomers.

The key role of chiral small molecules in drug discovery programs has been deeply investigated throughout last decades. In this context, our previous studies highlighted the influence of the absolute configuration of different stereocenters on the pharmacokinetic, pharmacodynamic and functional properties of promising Sigma receptor (SR) modulators. Thus, starting from the racemic SR ligand RC752, we report herein the isolation of the enantiomers via enantioselective separation with both HPLC and SFC.

Synthesis and Biological Evaluation of Enantiomerically Pure () and ()[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors.

GluN2B subunit-containing methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ()[F]OF-NB1 and ()[F]OF-NB1 as well as to assess their and performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents.

Diastereoselective synthesis and structure-affinity relationships of receptor ligands with spirocyclic scaffold.

Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different α,β-unsaturated amides 6 and 13-16 with methyl acrylate in the presence of TBDMSOTf.

Negative allosteric modulators of NMDA receptors with GluN2B subunit: synthesis of β-aminoalcohols by epoxide opening and subsequent rearrangement.

In order to obtain novel antagonists of GluN2B subunit containing NMDA receptors, aryloxiranes were opened with benzylpiperidines. Phenyloxiranes 6 and (indazolyl)oxirane 15 were opened regioselectively at the position bearing the aryl moiety. Reaction of the resulting β-aminoalcohols 7 and 16 with carboxylic acids under Mitsunobu conditions (DIAD, PPh) led to rearrangement and after ester hydrolysis to the regioisomeric β-aminoalcohols 9 and 18.

Indazole as a Phenol Bioisostere: Structure-Affinity Relationships of GluN2B-Selective NMDA Receptor Antagonists.

Negative allosteric modulation of GluN2B subunit-containing NMDA receptors prevents overstimulation, resulting in neuroprotective effects. Since the phenol of prominent negative allosteric modulators is prone to rapid glucuronidation, its bioisosteric replacement by an indazole was envisaged. The key step in the synthesis was a Sonogashira reaction of non-protected iodoindazoles with propargylpiperidine derivatives.

Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives.

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications.

Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain.

Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world's population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs.

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes.

The number of -Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer's disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options.

Conformationally Restricted σ Receptor Antagonists from (-)-Isopulegol.

Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and transformed into bicyclic and tricyclic ligands . Aminodiols showed higher σ affinity than the corresponding bicyclic and tricyclic derivatives .

Molecular mechanism of biased signaling at the kappa opioid receptor.

The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays.

The second PI(3,5)P binding site in the helix of KCNQ1 stabilizes PIP-at the primary site with potential consequences on intermediate-to-open state transition.

The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P), a known regulator of membrane protein trafficking. PI(3,5)P facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. Functional-physical interaction of PI(3,5)P with membrane proteins and its structural impact is not sufficiently understood.

Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation.

Modulation of two-pore domain potassium (K) channels has emerged as a novel field of therapeutic strategies as they may regulate immune cell activation and metabolism, inflammatory signals, or barrier integrity. One of these ion channels is the TWIK-related potassium channel 1 (TREK1). In the current study, we report the identification and validation of new TREK1 activators.

Synthesis and Biological Evaluation of Enantiomerically Pure ()- and ()-[F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors.

GluN2B subunit-containing -methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation.

Synthesis and Functional Characterization of Novel RU1968-Derived CatSper Inhibitors with Reduced Stereochemical Complexity.

The sperm-specific Ca channel CatSper (cation channel of sperm) controls the intracellular Ca concentration and, thereby, the swimming behavior of sperm from many species. The steroidal ethylenediamine RU1968 () represents a well-characterized, potent, and fairly selective cross-species inhibitor of CatSper. Due to its two additional centers of chirality in the amine-bearing side chain, RU1968 is a mixture of diastereomeric pairs of enantiomers and, thus, difficult to synthesize.