The E3 ligase TaGW2 mediates transcription factor TaARR12 degradation to promote drought resistance in wheat.

Drought stress limits crop yield, but the molecular modulators and their mechanisms underlying the trade-off between drought resistance and crop growth and development remain elusive. Here, a grain width and weight2 (GW2)-like really interesting new gene finger E3 ligase, TaGW2, was identified as a pivotal regulator of both kernel development and drought responses in wheat (Triticum aestivum). TaGW2 overexpression enhances drought resistance but leads to yield drag under full irrigation conditions. In contrast, TaGW2 knockdown or knockout attenuates drought resistance but remarkably increases kernel size and weight. Furthermore, TaGW2 directly interacts with and ubiquitinates the type-B Arabidopsis response regulator TaARR12, promoting its degradation via the 26S proteasome. Analysis of TaARR12 overexpression and knockdown lines indicated that TaARR12 represses the drought response but does not influence grain yield in wheat. Further DNA affinity purification sequencing combined with transcriptome analysis revealed that TaARR12 downregulates stress-responsive genes, especially group-A basic leucine zipper (bZIP) genes, resulting in impaired drought resistance. Notably, TaARR12 knockdown in the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9)-mediated tagw2 knockout mutant leads to significantly higher drought resistance and grain yield compared to wild-type plants. Collectively, these findings show that the TaGW2-TaARR12 regulatory module is essential for drought responses, providing a strategy for improving stress resistance in high-yield wheat varieties.

A gain-of-function allele of a DREB transcription factor gene ameliorates drought tolerance in wheat.

Drought is a major environmental factor limiting wheat production worldwide. However, the genetic components underlying wheat drought tolerance are largely unknown. Here, we identify a DREB transcription factor gene (TaDTG6-B) by genome-wide association study that is tightly associated with drought tolerance in wheat. Candidate gene association analysis revealed that a 26-bp deletion in the TaDTG6-B coding region induces a gain-of-function for TaDTG6-BDel574, which exhibits stronger transcriptional activation, protein interactions, and binding activity to dehydration-responsive elements (DRE)/CRT cis-elements than the TaDTG6-BIn574 encoded by the allele lacking the deletion, thus conferring greater drought tolerance in wheat seedlings harboring this variant. Knockdown of TaDTG6-BDel574 transcripts attenuated drought tolerance in transgenic wheat, whereas its overexpression resulted in enhanced drought tolerance without accompanying phenotypic abnormalities. Furthermore, the introgression of the TaDTG6-BDel574 elite allele into drought-sensitive cultivars improved their drought tolerance, thus providing a valuable genetic resource for wheat breeding. We also identified 268 putative target genes that are directly bound and transcriptionally regulated by TaDTG6-BDel574. Further analysis showed that TaDTG6-BDel574 positively regulates TaPIF1 transcription to enhance wheat drought tolerance. These results describe the genetic basis and accompanying mechanism driving phenotypic variation in wheat drought tolerance, and provide a novel genetic resource for crop breeding programs.

Application of TiLOOP bra in implant-based breast reconstruction is associated with decreased complication risk compared with other meshes: A systematic review and meta-analysis.

BACKGROUND: TiLOOP bra has been used for over 15 years, however, evidence regarding its safety in implant-based breast reconstruction (IBBR) for patients with breast cancer after mastectomy is still limited. We performed this meta-analysis to evaluate its risks and benefits in IBBR comparing with other meshes. METHODS: Electronic databases were searched to identify relevant studies comparing postoperative complications between TiLOOP bra and other reconstruction techniques in IBBR with or without meshes. We also compared patient satisfaction in physical well-being between two groups. Risk ratios (RRs) and mean differences with 95% confidence interval (CI) were calculated. RESULTS: Seven studies representing 1203 cases were analyzed. Compared with other meshes, the use of TiLOOP bra significantly reduced the risk of infection (RR = 0.53, 95% CI, 0.32-0.86), seroma (RR = 0.21, 95% CI, 0.07-0.61), red breast syndrome (RR = 0.10, 95% CI, 0.02-0.45), and capsular contracture (RR = 0.20, 95% CI, 0.05-0.75). Patient satisfaction in physical well-being was comparable between two groups. CONCLUSIONS: TiLOOP bra in IBBR has a favored safety profile over other meshes, which significantly reduced postoperative complication risk and did not affect patient satisfaction. Although prospective well-designed controlled studies are still warranted, TiLOOP bra is safe and reliable at present.

Transcription Factor 21: A Transcription Factor That Plays an Important Role in Cardiovascular Disease.

BACKGROUND: According to the World Health Organisation's Health Report 2019, approximately 17.18 million people die from cardiovascular disease each year, accounting for more than 30% of all global deaths. Therefore, the occurrence of cardiovascular disease is still a global concern. The transcription factor 21 (TCF21) plays an important role in cardiovascular diseases. This article reviews the regulation mechanism of TCF21 expression and activity and focuses on its important role in atherosclerosis in order to contribute to the development of diagnosis and treatment of cardiovascular diseases. SUMMARY: TCF21 is involved in the phenotypic regulation of vascular smooth muscle cells (VSMCs), promotes the proliferation and migration of VSMCs, and participates in the activation of inflammatory sequences. Increased proliferation and migration of VSMCs can lead to neointimal hyperplasia after vascular injury. Abnormal hyperplasia of neointima and inflammation are one of the main features of atherosclerosis. Therefore, targeting TCF21 may become a potential treatment for relieving atherosclerosis. KEY MESSAGES: TCF21 as a member of basic helix-loop-helix transcription factors regulates cell growth and differentiation by modulating gene expression during the development of different organs and plays an important role in cardiovascular development and disease. VSMCs and cells derived from VSMCs constitute the majority of plaques in atherosclerosis. TCF21 plays a key role in regulation of VSMCs' phenotype, thus accelerating atherogenesis in the early stage. However, TCF21 enhances plaque stability in late-stage atherosclerosis. The dual role of TCF21 should be considered in the translational medicine.

Safety and efficacy of apixaban versus vitamin K antagonists in patients undergoing dialysis: a systematic review and meta-analysis.

BACKGROUND: This review aims to evaluate the safety and efficacy of apixaban vs. vitamin K antagonists (VKAs) in patients on dialysis. METHODS: All types of studies published on PubMed, Embase, CENTRAL, and Web of Science up to 10 September 2023 and comparing outcomes of apixaban vs. VKA in dialysis patients were eligible. RESULTS: Two randomized controlled trials (RCTs) and six retrospective studies were included. Apixaban treatment was associated with significantly lower risk of major bleeding (RR: 0.61; 95% CI: 0.48, 0.77; I2 = 50%) and clinically relevant non-major bleeding (RR: 0.82, 95% CI: 0.68, 0.98, I2 = 9%) compared to VKA. Meta-analysis also showed that the risk of gastrointestinal bleeding (RR: 0.74, 95% CI: 0.64, 0.85, I2 = 16%) and intracranial bleeding (RR: 0.64, 95% CI: 0.49, 0.84, I2 = 0%) was significantly reduced with apixaban. Meta-analysis showed no difference in the risk of ischemic stroke (RR: 0.40, 95% CI: 0.06, 2.69, I2 = 0%), mortality (RR: 1.26, 95% CI: 0.74, 2.16, I2 = 94%) and recurrent venous thromboembolism (RR: 1.02, 95% CI: 0.87, 1.21, I2 = 0%) between the two groups. Subgroup analysis of RCTs showed no difference in bleeding outcomes. CONCLUSIONS: Low-quality evidence from a mix of RCTs and retrospective studies shows that apixaban may have better safety and equivalent efficacy as compared to VKA in dialysis patients. Apixaban treatment correlated with significantly reduced risk of major bleeding and clinically relevant nonmajor bleeding in observational studies but not in RCTs. The predominance of retrospective data warrants caution in the interpretation of results.

Do oral antidiabetic medications alter the risk of Parkinson's disease? An updated systematic review and meta-analysis.

BACKGROUND: Diabetes mellitus is a known risk factor for Parkinson's disease (PD), but does this risk vary with antidiabetic medications is still unclear. This meta-analysis aims to compile evidence from the literature to assess the risk of idiopathic PD with various oral antidiabetic medications. METHODS: Databases PubMed, CENTRAL, Scopus, Web of Science, and Embase were searched till 5th April 2023. Adjusted outcomes were pooled to generate a hazard ratio (HR) on the risk of PD with different antidiabetic medications. RESULTS: Fifteen studies with 2,910,405 diabetic patients were eligible. Pooled analysis failed to show any significant difference in the risk of PD among users of metformin (HR: 1.05 95% CI: 0.91, 1.22 I2 = 81%), glitazones (HR: 0.84 95% CI: 0.68, 1.05 I2 = 91%), glucagon-like peptide-1 agonists (HR: 0.63 95% CI: 0.26, 1.55 I2 = 33%), and sulfonylureas (HR: 1.13 95% CI: 0.96, 1.32 I2 = 76%). However, a meta-analysis of four studies showed that dipeptidyl peptidase-4 inhibitor use was associated with reduced risk of PD in diabetics (HR: 0.69 95% CI: 0.56, 0.86 I2 = 46%). Insufficient data was available on sodium-glucose cotransporter-2 inhibitors, α-glucosidase inhibitors, and glinides. CONCLUSIONS: Limited retrospective evidence indicates that DPP4i may reduce the risk of idiopathic PD in diabetics. Metformin, sulfonylureas, glucagon-like peptide-1 agonists, and glitazones were not associated with any change in the risk of PD. Further studies taking into confounding factors and using a common comparator group are needed to strengthen present evidence.

Effectiveness of Tai Chi exercise on fear of falling and balance in older adults: A meta-analysis.

OBJECTIVE: To assess the effect of Tai Chi exercise on fear of falling (FOF) and balance in older adults. METHOD: Chinese and English databases were searched for randomized controlled trials (RCTs) on the effect of Tai Chi on the fear of falling and balance of older adults. The search time limit was from inception until 13 December 2022. RESULTS: A total of 13 RCTs were included and the overall quality was moderate. The results showed that Tai Chi exercise could significantly improve fear of falling [SMD = -0.54, 95%CI(-1.09, 0.01), Z =1.94, P = 0.05], dynamic balance [SMD = -2.23, 95%CI(-3.89, -0.75), Z=2.90, P = 0.004] and fall incidence [RR = 0.48, 95%CI(0.35, 0.65), Z =4.67, P <0.001] in older adults. However, its significant benefits in improving the static balance [MD = 4.16, 95%CI(-3.71, 12.04), Z =1.04, P = 0.30] in older adults were not found. The results of the subgroup analysis showed that the short-term effect of Tai Chi in reducing the fear of falling was more significant (P = 0.002). CONCLUSION: Tai Chi could alleviate the FOF of older adults, improve balance and reduce fall incidence. However, large-sample, multi-center, high-quality randomized controlled studies are still verified in the future.

The wheat ABA receptor gene TaPYL1-1B contributes to drought tolerance and grain yield by increasing water-use efficiency.

The role of abscisic acid (ABA) receptors, PYR1/PYL/RCAR (PYLs), is well established in ABA signalling and plant drought response, but limited research has explored the regulation of wheat PYLs in this process, especially the effects of their allelic variations on drought tolerance or grain yield. Here, we found that the overexpression of a TaABFs-regulated PYL gene, TaPYL1-1B, exhibited higher ABA sensitivity, photosynthetic capacity and water-use efficiency (WUE), all contributed to higher drought tolerance than that of wild-type plants. This heightened water-saving mechanism further increased grain yield and protected productivity during water deficit. Candidate gene association analysis revealed that a favourable allele TaPYL1-1BIn-442 , carrying an MYB recognition site insertion in the promoter, is targeted by TaMYB70 and confers enhanced expression of TaPYL1-1B in drought-tolerant genotypes. More importantly, an increase in frequency of the TaPYL1-1BIn-442 allele over decades among modern Chinese cultivars and its association with high thousand-kernel weight together demonstrated that it was artificially selected during wheat improvement efforts. Taken together, our findings illuminate the role of TaPYL1-1B plays in coordinating drought tolerance and grain yield. In particular, the allelic variant TaPYL1-1BIn-442 substantially contributes to enhanced drought tolerance while maintaining high yield, and thus represents a valuable genetic target for engineering drought-tolerant wheat germplasm.

Genome-wide association study revealed TaHXK3-2A as a candidate gene controlling stomatal index in wheat seedlings.

Stomata are important channels for the control of gas exchange between plants and the atmosphere. To examine the genetic architecture of wheat stomatal index, we performed a genome-wide association study (GWAS) using a panel of 539 wheat accessions and 450 678 polymorphic single nucleotide polymorphisms (SNPs) that were detected using wheat-specific 660K SNP array. A total of 130 SNPs were detected to be significantly associated with stomatal index in both leaf surfaces of wheat seedlings. These significant SNPs were distributed across 16 chromosomes and involved 2625 candidate genes which participate in stress response, metabolism and cell/organ development. Subsequent bulk segregant analysis (BSA), combined with GWAS identified one major haplotype on chromosome 2A, that is responsible for stomatal index on the abaxial leaf surface. Candidate gene association analysis revealed that genetic variation in the promoter region of the hexokinase gene TaHXK3-2A was significantly associated with the stomatal index. Moreover, transgenic analysis confirmed that TaHXK3-2A overexpression in wheat decreased the size of leaf pavement cells but increased stomatal density through the glucose metabolic pathway, resulting in drought sensitivity among TaHXK3-2A transgenic lines due to an increased transpiration rate. Taken together, these results provide valuable insights into the genetic control of the stomatal index in wheat seedlings.

Mechanistic Insights into Fast Charging and Discharging of the Sodium Metal Battery Anode: A Comparison with Lithium.

Na metal anode receives increasing attention as a low-cost alternative to Li metal anode for the application in high energy batteries. Despite extensive research efforts to improve the reversibility and cycle life of Na metal electrodes, their rate performance, i.e. electrochemical plating and stripping of Na metal at high current, is underexplored. Herein, we report that Na metal electrodes, unlike the more widely studied Li metal electrodes which survive high current density up to 20 mA/cm2, cannot be fast charged or discharged in common ether electrolyte. The fast charging, namely metal plating, is comprised by severe side reactions that decompose electrolyte into electrochemically inactive Na(I) solid species. The fast discharging, namely metal stripping, is disabled by local Na removal that deteriorates the electrical contact with the current collector. While the fast charging failure is permanent, the capacity loss from fast discharging can be recovered through a restructuring process at a low discharging current which rebuilds the electrical connection. We further reveal that the unsatisfactory rate performance of Na metal electrodes is associated with intrinsic physicochemical properties of Na. This study delineates the mechanistic origins of Na's limitation in fast plating and stripping, and demonstrates the necessity of improving the charging and discharging rate performance of Na metal electrodes.

Elevated expression of LPCAT1 predicts a poor prognosis and is correlated with the tumour microenvironment in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is one of the three malignant reproductive tumours that threaten women's lives and health. Glycerophospholipids (GPLs) are important bioactive lipids involved in various physiological and pathological processes, including cancer. Immune infiltration of the tumour microenvironment (TME) is positively associated with the overall survival in EC. Exploring GPL-related factors associated with the TME in endometrial cancer can aid in the prognosis of patients and provide new therapeutic targets. METHODS: Differentially expressed GPL-related genes were identified from TCGA-UCEC datasets and the Molecular Signatures Database (MSigDB). Univariate Cox regression analysis was used to select GPL-related genes with prognostic value. The Random forest algorithm, LASSO algorithm and PPI network were used to identify critical genes. ESTIMATEScore was calculated to identify genes associated with the TME. Then, differentiation analysis and survival analysis of LPCAT1 were performed based on TCGA datasets. GSE17025 and immunohistochemistry (IHC) verified the results of the differentiation analysis. An MTT assay was then conducted to determine the proliferation of EC cells. GO and KEGG enrichment analyses were performed to explore the underlying mechanism of LPCAT1. In addition, we used the ssGSEA algorithm to explore the correlation between LPCAT1 and cancer immune infiltrates. RESULTS: Twenty-three differentially expressed GPL-related genes were identified, and eleven prognostic genes were selected by univariate Cox regression analysis. Four significant genes were identified by two different algorithms and the PPI network. Only LPCAT1 was significantly correlated with the tumour microenvironment. Then, we found that LPCAT1 was highly expressed in tumour samples compared with that in normal tissues, and lower survival rates were observed in the groups with high LPCAT1 expression. Silencing of LPCAT1 inhibited the proliferation of EC cells. Moreover, the expression of LPCAT1 was positively correlated with the histologic grades and types. The ROC curve indicated that LPCAT1 had good prognostic accuracy. Receptor ligand activity, pattern specification process, regionalization, anterior/posterior pattern specification and salivary secretion pathways were enriched as potential targets of LPCAT1. By using the ssGSEA algorithm, fifteen kinds of tumor-infiltrating cells (TICs) were found to be correlated with LPCAT1 expression. CONCLUSION: These findings suggested that LPCAT1 may act as a valuable prognostic biomarker and be correlated with immune infiltrates in endometrial cancer, which may provide novel therapy options for and improved treatment of EC.

Metal-free, oxidative decarboxylation of aryldifluoroacetic acid with the formation of the ArS-CF2 bond.

A metal-free, oxidative decarboxylative reaction of aryldifluoroacetic acids with diaryl disulfides or thiols under mild reaction conditions has been developed. This is an efficient and straightforward radical cross-coupling method for the synthesis of diverse aryldifluoromethylthio ethers in moderate to excellent yields.

Visible-light mediated stereospecific C(sp2)-H difluoroalkylation of (Z)-aldoximes.

A visible light mediated stereospecific C(sp2)-H difluoroalkylation of (Z)-aldoximes to (E)-difluoroalkylated ketoximes has been described. In this reaction, (hetero)-aromatic and aliphatic difluoroalkylated ketoximes could be obtained with the retention of the configuration of the starting aldoximes. A preliminary mechanism study showed that a difluoromethyl radical via an SET pathway was involved.

Genome-wide analysis of the AREB/ABF gene lineage in land plants and functional analysis of TaABF3 in Arabidopsis.

BACKGROUND: Previous studies have shown that ABFs (abscisic acid-responsive transcription factors) are important ABA-signaling components that participate in abiotic stress response. However, little is known about the function of ABFs in Triticum aestivum. In addition, although various ABFs have been identified in other species, the phylogenetic relationship between ABF transcription factors has not been systemically investigated in land plants. RESULTS: In this study, we systemically collected ABFs from land plants and analyzed the phylogenetic relationship of these ABF genes. The ABF genes are present in all the land plants we investigated, including moss, lycophyte, monocots, and eudicots. Furthermore, these ABF genes are phylogenetically divided into seven subgroups, differentiations that are supported by variation in the gene structure, protein properties, and motif patterns. We further demonstrated that the expression of ABF genes varies among different tissues and developmental stages, and are induced by one or more environmental stresses. Furthermore, we found that three wheat ABFs (TaABF1, TaABF2, and TaABF3) were significantly induced by drought stress. Compared with wild-type (WT) plants, transgenic Arabidopsis plants overexpressing TaABF3 displayed enhanced drought tolerance. CONCLUSIONS: These results provide important ground work for understanding the phylogenetic relationships between plant ABF genes. Our results also indicate that TaABFs may participate in regulating plant response to abiotic stresses.

Ag-Catalyzed minisci C-H difluoromethylarylation of N-heteroarenes.

A mild silver-catalyzed decarboxylative difluoromethylarylation of electron-deficient N-heteroarenes has been developed by using aryldifluoro acetic acid as difluoromethyl sources. This protocol provides an efficient and straightforward access to difluoromethylated heteroarenes in moderate to excellent yields with good selectivities. Furthermore, this reaction was applicable to bioactive heteroarenes, providing a straightforward approach for the late-stage C-H difluoromethylation of pharmacophores.

Molecular epidemiology and genetic variation analyses of porcine circovirus type 2 isolated from Yunnan Province in China from 2016-2019.

BACKGROUND: Porcine circovirus type 2 (PCV2) is the causative agent of porcine circovirus-associated disease (PCVAD). Its prevalence in swine herds was first reported in China in 2000. PCV2 infection causes immunosuppression that leads to multiple diseases, causing serious economic problems for the swine industry in China. Since information on the genetic variation of PCV2 in Yunnan province is limited, this study aims to investigate the molecular epidemiological and evolutionary characteristics of PCV2 from 2016 to 2019. METHODS: A total of 279 clinical samples were collected from different regions of Yunnan between 2016 to 2019, and PCV2 was detected by PCR. We then amplified full genomes from the positive samples, and the sequences were analysed for homology and genetic evolution. RESULTS: Overall, 60.93% (170/279) of the screened swine herd samples were positive for PCV2. We sequenced 15 Yunnan province PCV2 strains from positive samples. Analyses of the complete genomes and Cap genes led to the classification of the 15 Yunnan PCV2 strains into PCV2a (2 of 15), PCV2b (1of 15) and PCV2d (12 of 15). All strains shared 94.3-99.9% of their identities with the nucleotide sequences of complete genomes in this study and shared 94.2-99.9% identity with the reference sequences. All strains share 89.4-100% and 86.8-100% of their identities with the nucleotide and amino acid (aa) sequences of Cap, respectively. CONCLUSIONS: The results of this study provide evidence that PCV2a, PCV2b and PCV2d genotypes coexisted in Yunnan Province from 2016 to 2019, and the priority prevalence genotype was PCV2d. The data provide evidence for the increased genetic diversity and insights into the molecular epidemiology of PCV2. This study also provides basic data for the Yunnan province PCV2 molecular epidemiological survey and accumulates effective materials for the development of PCV2 vaccines.

Comparison and application of two microextractions based on syringe membrane filter.

Two proposed syringe membrane filter solid phase microextraction and syringe membrane filter liquid/solid phase microextraction, coupled separately with high performance liquid chromatography, were developed for simultaneous enrichment and determination of the trace level of flavonoids in traditional Chinese medicine. In syringe membrane filter solid phase microextraction, the membrane of syringe membrane filter was served as a solid adsorption film to adsorb target analytes. And in syringe membrane filter liquid/solid phase microextraction, the membrane of syringe membrane filter was used as not only an adsorption phase, but also as a holder of extraction solvent to realize liquid-solid synergistic extraction. The simple operation, rapid extraction, and little or no organic solvent consumption make the two approaches very interesting. To evaluate the two proposed approaches, the crucial parameters affecting the enrichment factors of target analytes were investigated and optimized, and the two microextractions were intercompared. Moreover, their microextraction mechanisms were analyzed and described. Under the optimized conditions, both the new approaches achieved good linearities, accuracies, precisions, and low limits of detection, and the two methods were successfully applied for concentration of the flavonoids in traditional Chinese medicines.

Solvent Molecule Cooperation Enhancing Lithium Metal Battery Performance at Both Electrodes.

Developing electrolytes compatible with efficient and reversible cycling of electrodes is critical to the success of rechargeable Li metal batteries (LMBs). The Coulombic efficiencies and cycle lives of LMBs with ethylene carbonate (EC), dimethyl carbonate, ethylene sulfite (ES), and their combinations as electrolyte solvents show that in a binary-solvent electrolyte the extent of electrolyte decomposition on the electrode surface is dependent on the solvent component that dominates the solvation sheath of Li+ . This knowledge led to the development of an EC-ES electrolyte exhibiting high performance for Li||LiFePO4 batteries. Carbonate molecules occupy the solvation sheath and improve the Coulombic efficiencies of both the anode and cathode. Sulfite molecules lead to desirable morphology and composition of the solid electrolyte interphase and extend the cycle life of the Li metal anode. The cooperation between these components provides a new example of electrolyte optimization for improved LMBs.

Paraffin Oil Based Soft-Template Approach to Fabricate Reusable Porous PDMS Sponge for Effective Oil/Water Separation.

Three-dimensional porous material holds enormous potential in the field of life science and environmental protection. In this work, we proposed a facile route for the large-scale synthesis of porous poly(dimethylsiloxane) (PDMS) sponge via paraffin oil based emulsion technique. A stable emulsion could be formed by emulsifying water in the PDMS solution with the aid of paraffin oil. Moreover, the amount of emulsified water in 5 g of PDMS solution is as high as 35 g, and the skeleton of the prepared PDMS sponge is still in intact. This method is cost-effective, rapid, and easily scaled up. The water contact angle of the obtained PDMS sponge is 141.9 ± 1°, and the absorption capacities of the sponges are 13.5-33.3 g g-1 for various organic solvents. The PDMS sponge only needed 0.069 MPa force to realize the compression ratio of 90%, which it still maintained after over 50 cycles of compression. In addition, the porous PDMS sponge exhibited an excellent oil absorption and an outstanding reusability, which were potentially useful in water purification.

Synthesis and Biological Evaluation of Sigma-1 (σ1 ) Receptor Ligands Based on Phenyl-1,2,4-oxadiazole Derivatives.

In this study, a series of phenyl-1,2,4-oxadiazole derivatives were synthesized and evaluated for anti-allodynic activity. Structure-activity relationship studies identified 1-{4-[3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl]butyl}piperidine (39) with excellent affinity for the σ1 receptor and selectivity for the σ2 receptor, with poor activity to other central nervous system neurotransmitter receptors and transporters associated with pain. Compound 39 exhibited dose-dependent efficacy in suppressing the formalin-induced flinching and attenuating mechanical allodynia in chronic constriction injury-induced neuropathic rats. These results suggest that compound 39 exerts potent antihyperalgesic activity and could be considered as a promising candidate for treating neuropathic pain.