Synthesis and Biological Evaluation of Novel Biased Mu-Opioid Receptor Agonists.

This study explored the potential of a series of PZM21 analogues for pain treatment. Specifically, the hydroxyphenyl ring of PZM21 was replaced with a naphthyl ring, the thienyl ring was substituted with either a phenyl ring or furan rings, and the essential dimethylamine and urea groups were retained. These compounds aimed to enhance safety and minimize the adverse effects associated with opioid drugs. The research findings suggest that compound 6a does not induce ß-arrestin recruitment at low-nanomolar concentrations but exhibits significant analgesic effects in established mouse models. Compared to morphine, 6a shows advantages in alleviating respiratory depression and minimizing physical dependence. Molecular docking studies underscore the pivotal role of the D147 amino acid residue in the analgesic mechanism of 6a. Consequently, 6a is a compelling candidate for the development of safer opioid analgesics and warrants further attention.

Discovery and Structural Explorations of G-Protein Biased µ-Opioid Receptor Agonists.

Compounds that activate only the G-protein signalling pathway represent an effective strategy for making safer opioids. In the present study, we report the design, synthesis and evaluation of two classes of novel PZM21 derivatives containing the benzothiophene ring and biphenyl ring group respectively as biased µ-opioid receptor (µOR) agonists. The new compound SWG-LX-33 showed potent µOR agonist activity and produced µOR-dependent analgesia. SWG-LX-33 does not activate the ß-arrestin-2 signalling pathway in vitro even at high concentrations. Computational docking demonstrated the amino acid residue ASN150 to be critical for the weak efficacy and potency of µOR agonists in arrestin recruitment.

Surface-Fe enriched trimetallic (oxy)hydroxide engineered by S-incorporation and ligand anchoring toward efficient water oxidation.

Surface Fe with low-coordination plays a decisive role in the performance of OER catalysts in basic media, however, it is still a huge challenge to construct a Fe-enriched surface. Herein, a novel S-incorporation and ligand anchoring strategy is reported for in-situ synthesis of surface-Fe enriched OER catalysts. During the OER test, the co-etching of S elements and ligands enables the formation of surface-Fe enriched trimetallic (oxy)hydroxide OER catalysts. Benefiting from the high catalytic activity of Fe enriched species on surface, the electrode delivers an ultralow overpotential of 234 mV to reach the current density of 10 mA cm-2 and a superior stability over 50 h. This efficient S-incorporation and ligand anchoring strategy offers a new perspective for in-situ construction of advanced earth-abundant OER catalysts.