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.

π-Extended Nonfullerene Acceptor for Compressed Molecular Packing in Organic Solar Cells To Achieve over 20% Efficiency.

Organic photovoltaics (OPVs) suffer from a trade-off between efficient charge transport and suppressed nonradiative recombination due to the aggregation-induced luminance quenching of organic semiconductors. To resolve this grand challenge, a π-extended nonfullerene acceptor (NFA) B6Cl with large voids among the honeycomb network is designed and introduced into photovoltaic systems. We find that the presence of a small amount of (i.e., 0.5 or 1 wt %) B6Cl can compress the molecular packing of the host acceptor L8-BO, leading to shortened π-π stacking distance from 3.59 to 3.50 Å (that will improve charge transport) together with ordered alkyl chain packing (that will inhibit nonradiative energy loss due to the suppressed C-C and C-H bonds vibrations), as validated by high-energy X-ray scattering measurements. This morphology transformation ultimately results in simultaneously improved JSC, FF, and VOC of OPVs. As a result, the maximum PCEs of PM6:L8-BO and D18:L8-BO are increased from 19.1 and 19.3% to 19.8 and 20.2%, respectively, which are among the highest values for single-junction OPVs. The university of B6Cl to increase the performance of OPVs is further evidenced in a range of polymer:NFA OPVs.

Alkoxythiophene-Directed Fibrillization of Polymer Donor for Efficient Organic Solar Cells.

Realizing fibrillar molecular framework is highly encouraged in organic solar cells (OSCs) due to the merit of efficient charge carrier transport. This is however mainly achieved via the chemical structural design of photovoltaic semiconductors. In this work, through the utilization of three alkoxythiophene additives, T-2OMe, T-OEH, and T-2OEH, the intermolecular interactions among a series of BDT-type polymer donors, i.e., PM6, D18, PBDB-T, and PTB7-Th, are tuned to self-assemble into nanofibrils during solution casting. X-ray technique and molecular dynamics simulation reveal that the alkoxythiophene with (2-ethylhexyl)oxy (─OEH) chains can attach on the 2-ethylhexyl (EH) chains of these polymer donors and promote their self-assembly into 1D nanofibrils, in their neat films as well as photovoltaic blends with L8-BO. By adapting these fibrillar polymer donors to construct pseudo-bulk heterojunction (P-BHJ) OSCs via layer-by-layer deposition, generally improved device performance is seen, with power conversion efficiencies enhanced from 18.2% to 19.2% (certified 18.96%) and from 17.9% to 18.7% for the PM6/L8-BO and D18/L8-BO devices, respectively. This work provides a physical approach to promote the fibrillar charge transport channels for efficient photovoltaics.

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.

Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain.

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.

Improved Production of Pyrroloquinoline Quinone by Simultaneous Augmentation of Its Synthesis Gene Expression and Glucose Metabolism in Klebsiella pneumoniae.

Klebsiella pneumoniae can naturally synthesize pyrroloquinoline quinone (PQQ), but current low yield restricts its commercialization. Here, we reported that PQQ production can be improved by simultaneously intensifying PQQ gene expression and glucose metabolism. Firstly, tandem repetitive tac promoters were constructed to overexpress PQQ synthesis genes. Results showed that when three repeats of tac promoter were recruited to overexpress PQQ synthesis genes, the recombinant strain generated 1.5-fold PQQ relative to the strain recruiting only one tac promoter. Quantitative real-time PCR (qRT-PCR) revealed the increased transcription levels of PQQ synthesis genes. Next, fermentation parameters were optimized to augment the glucose direct oxidation pathway (GDOP) mediated by PQQ-dependent glucose dehydrogenase (PQQ-GDH). Results demonstrated that the cultivation conditions of sufficient glucose (≥ 32 g/L), low pH (5.8), and limited potassium (0.7 nmol/L) significantly promoted the biosynthesis of gluconic acid, 2-ketogluconic acid, and PQQ. In optimum shake flask fermentation conditions, the K. pneumoniae strain overexpressing PQQ synthesis genes under three repeats of tac promoter generated 363.3 nmol/L of PQQ, which was 2.6-fold of that in original culture conditions. In bioreactor cultivation, this strain produced 2371.7 nmol/L of PQQ. To our knowledge, this is the highest PQQ titer reported so far using K. pneumoniae as a host strain. Overall, simultaneous intensification of pqq gene expression and glucose metabolism is effective to improve PQQ production.

Discovery of Biased Mu-Opioid Receptor Agonists for the Treatment of Pain.

G protein-biased mu-opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-phenethylurea) and 7 j ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less ß-arrestin-2 recruitment.

Synthesis and Evaluation of Novel Biased µ-Opioid-Receptor (µOR) Agonists.

'Biased' ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent µ-opioid-receptor (µOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable ß-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased µOR agonists for treating pain.

Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain.

The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted.