The δ-opioid receptor (DOR) continues to attract attention as a therapeutic target for the development of safer analgesics due to its ability to mediate pain relief with a lower risk of adverse effects compared to the μ-opioid receptor (MOR). Building upon our previous findings on KNT-127, a DOR-selective agonist with a morphinan scaffold, this study further explores the structure–signal relationships between quinoline ring modifications and the signaling bias toward Gi-protein activation while minimizing β-arrestin-2 recruitment. Our findings highlight the critical role of the 5′-position in modulating signaling bias. Bulky hydrophobic substituents, such as isopropoxy and cyclohexanoxy groups, effectively reduce β-arrestin-2 recruitment without compromising DOR binding affinity or Gi-protein activation. Molecular-docking and molecular dynamics simulations provided mechanistic insights, showing that these modifications change ligand interactions with the V281^6.55-W284^6.58-L300^7.35 sub-pocket, thus selectively favoring Gi-protein signaling. These insights clarify the key interactions for the signaling bias in DOR agonists, offering a new framework for the design of DOR-targeted therapies with an improved therapeutic profile.

The pandemic of coronavirus disease 2019, caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a serious concern worldwide. Although some effective vaccines have been developed, only a few anti-SARS-CoV-2 drugs have been approved for their clinical use. In this study, we designed and synthesized new anti-SARS-CoV-2 drugs based on the chemical structure of amodiaquine, which is known as an antimalarial drug. Consequently, we have identified amodiaquine analogs functionalized with dialkylamino-pendant aminophenol moieties that possess a high level of anti-SARS-CoV-2 activity with a low level of toxicity.

A concise approach is presented for preparing 4ʹ-modified thymidines from oxime imidates using readily generated 4ʹ-carbon radicals. This method produces 4ʹ-modified thymidines from natural thymidine using the Mitsunobu reaction, the protection of 3ʹ-hydroxy group (when necessary), and 1,5-hydrogen atom transfer (1,5-HAT)/intermolecular 1,4-addition with electron-deficient olefins. Moreover, using a one-pot synthesis involving 1,5-HAT/intermolecular 1,4-addition, followed by the hydrolysis of the imidate intermediate under basic conditions, 4′-modified thymidine was diastereoselectively isolated. This is because the 4′-isomer transferred to the water layer in the work-up process.

A squaramide organocatalyst was employed to efficiently promote asymmetric oxidative lactonization to construct spiro-fused 2-oxindoles in moderate-to-good yield and enantioselectivity (up to 81% enantiomeric excess (ee)). Herein, we report the first study accomplishing stereoselective oxidative cyclization from indole propionic acid using an organocatalyst, N-iodosuccinimide (NIS), and hydrogen peroxide under metal-free and mild reaction conditions.

Estrogen receptors (ERs) and their ligands regulate a variety of physiological processes in humans, and altered ER signaling is associated with serious disorders, including breast cancer. Estrogens also bind to other receptors such as G-protein-coupled receptor 30 (GPER), and so fluorescent estrogen ligands would be useful for various functional studies and for development of drug candidates. Here we describe fluorescent estrogen receptor ligands based on 3-aryl-7-hydroxycoumarin. Notably, these ligands also function as pH-dependent OFF-ON-OFF type fluorescent sensors, enabling the detection of specific ranges of pH.